THE UNIVERSITY OF CALGARY
Application of the Exorphin Hypothesis to Attention Deficit Hyperactivity Disorder:
A Theoretical Framework
by Ronald Hoggan
A THESIS SUBMITTED TO THE FACULTY OF GRADUATE STUDIES IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF ARTS GRADUATE DIVISION OF EDUCATIONAL RESEARCH
CALGARY, ALBERTA
APRIL, 1998
© Ronald Hoggan 1998
University of Calgary
THE UNIVERSITY OF CALGARY
FACULTY OF GRADUATE STUDIES
The undersigned certify that they have read, and recommend to the Faculty of Graduate Studies for acceptance, a thesis entitled , "Application of the Exorphin Hypothesis to Attention Deficit Hyperactivity Disorder: A Theoretical Framework" submitted by Ron Hoggan in partial fulfilment of the requirements for the degree of Master of Arts..
___________________________________
Supervisor, Anthony Marini, Ph.D.
Graduate Division of Educational Research
___________________________________
Sal Mandaglio, Ph.D.
Department of Educational Psychology
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Ashton Embry, Ph.D.
GLGP
__________________
Date
This document suggests that current practices which lead to the diagnosis and treatment of attention deficit hyperactivity disorder (ADHD) may obscure underlying pathologies which can have dangerous consequences when undiagnosed. While stimulant therapies are sometimes an effective tool for the short-term management of ADHD symptoms, they offer little long-term hope to the afflicted child, perhaps placing that person's health in serious jeopardy. Teacher involvement in this diagnostic and treatment process may aid in perpetuating this problem. An alternative understanding of ADHD, informed by the exorphin hypothesis, offers a safe, powerful tool for dealing with the underlying condition in many cases of ADHD, and an effective treatment for ADHD. A large and growing body of evidence supports the application of the exorphin hypothesis to ADHD, and points to some specific research needs in this area. Such research requires a shift away from the pharmacological paradigm, in recognition of distinctions between pharmaceutical and dietary interventions.
Preface
The possibility that exorphins may underlay many cases of ADHD is not a new perspective (Reichelt, Ekrem, Scott, 1990). What is offered here is an assembly of the various threads from peer reviewed, scientific literature, along with an integration of those threads into a tapestry which forms a compelling picture of what may constitute much of the condition we currently call ADHD. This thesis is informed and shaped by the growing body of peer reviewed literature which has increasingly pointed toward exorphins as a factor in ADHD (Reichelt et al., 1990; Crawford, Kaplan, Kinsbourne, 1994; Uhlig, Merkenschlager, Bandmaier, Egger, 1997). A variety of factors have contributed to the delayed emergence of this perspective regarding ADHD, including limited access to some of the literature in question, the absence of work which integrates the various elements of supporting evidence, and a language barrier which distances research findings from many of those who might benefit from knowledge of that medical and scientific information. An issue of limited availability of research funding may also have contributed to obscuring the applicability of the exorphin hypothesis to ADHD.
A variety of factors limit access to medical libraries, including their small numbers, hours of operation, and isolation from the community. Teaching hospitals have such libraries, but much of the public is unaware of their existence. Perhaps there is an intimidating air for the few who do manage to find such libraries.
Once access is gained, a further limiting factor is the scientific language in which research reports are written. This language obscures meaning to all who are not prepared or able to invest the necessary time required to master that language which is the medium of published medical and scientific reports. Part of the offering of this document is to provide an interpretation and an integration of these reports pertinent to the issue at hand..... ADHD.
What follows is offered in a form accessible to teachers and parents. The ultimate intent of this document is to aid children with ADHD, along with their parents, their teachers, and their medical caregivers through providing an alternative perspective of ADHD. Inherent in this view is a safe and effective alternative treatment for many, perhaps most, youngsters suffering from this condition.
The hypothesis embodied here is readily testable, and readers will judge for themselves whether the evidence presented warrants the expenditure of a very few dollars for serum antibody testing, or a few weeks of dietary investigation. The exorphin hypothesis suggests a broadly applicable set of principles which may also alleviate some of the current struggle to understand the underlying dynamics in a variety of psychiatric illnesses, including ADHD. It is also a postulation which offers an alternative, perhaps more appropriate path for teachers and parents who are disturbed by the behaviour of some of the children in their charge, but who recognize the fallacy underlying the current practice of administering powerful medications to children, thus reducing the unpleasant symptoms of ADHD, in the absence of a clear understanding of the condition being treated, or the therapeutic action of the drugs administered. The practice is one of placing some very dangerous band aids on symptoms without an understanding of the underlying cause of those symptoms.
Neither does this thesis or its author offer a claim of certainty in the representation of ADHD that follows. This hypothesis does offer a safe, effective, and healthy means of dealing with a majority of cases of ADHD, but it is recognized that there will be other causes in some cases of this condition. Also embodied here is an understanding which resolves many of the apparent anomalies in the medical and popular literature regarding this pervasive, debilitating condition that carries life-long implications regardless of the therapeutic intervention chosen.
Acknowledgements
This thesis reflects the love, support, and encouragement I've gotten from my wife, Betty, my mother, Edna, and my children, Donovan, Darren, Kari and Kyra. Their contributions have helped me find my way. It also reflects the mentoring, support, kindness, and understanding of my advisor, Dr. Anthony Marini. I am also grateful to Dr. Garth Benson for helping me see science through many windows, and see my angst as an impetus to explicate those windows. And finally, I am grateful to Dr. Jim Paul for helping me to understand understanding through the incongruent, dissonant, dichotomous metaphor of modernity, and through its counterpart.
Dedication
In memory of my brother, Jack Ernest Hoggan, June 17, 1946 to November 18, 1996. His pain inspired the work that lies before you. His death inscribed its meaning on my soul. May his passing light a better path for others.
Chapter One: Parents, Politicians, Physicians, Pedagogues, Pupils & Peptides
References [Moved to its own page]
Appendices:
Whereas there are several follow-up investigations of subjects who underwent lengthy courses of stimulant therapy, no significant long-term benefit from such therapies was reported (Barkley, 1977). This absence of long-term benefit may also be seen through comparing a 15 year follow-up of 63 hyperactive children who were not treated with stimulant therapy (Weiss, Hechtman, Milroy, Perlman, 1985), and a 12 year follow-up of 60 children, most of whom had undergone stimulant therapy (Claude, Firestone, 1995). Both groups had fared equally poorly when contacted at follow-up. Evidence of an associated delayed maturation of parts of the brain involved in executive function until the third decade of life, has also been reported (Castellanos 1997; Ucles, Lorente, Rosa, 1996). One such report also asserts that 52% of adolescent ADHD subjects display substance abuse and criminal behaviour (Castellanos 1997). This research contributes to a growing paradigm crisis (Kuhn 1970) in psychiatric and educational research. More and more children are being prescribed stimulant medications, yet only short-term benefits can be claimed for the majority sub-group of ADHD children who respond to such therapy. Conversely, an examination of dietary exorphins offers the possibility of a natural, long-term means to control symptoms and address the underlying pathology for many who suffer from ADHD. These exorphins are morphine-like peptides (Zioudrou, Streaty, Klee, 1979) which have been shown to result from the partial digestion of foods which have repeatedly been implicated in investigations of ADHD (Breakey, 1997).
In spite of some semantic difficulties, this delineation of features is identifying a very real and debilitating problem which most classroom teachers see daily. This latter assertion is based upon the 2% to 10% reported incidence of ADHD (Rowe 1988; Boris & Mandel 1994; Castellanos 1997). Our culture relies upon teachers and health care professionals to render appropriate instruction, accurate diagnoses, and effective treatment. This expectation may exceed reality. The risk of misdiagnosis, along with a singular reliance upon stimulant therapy, may simply constitute a short-term masking of the symptoms of physical ailments, and of the underlying causes of what may constitute most cases of ADHD. The teacher's and perhaps the clinician's familiarity with the diagnostic and differential features of ADHD may be hindered by the succession of changes to the various editions and revisions of the DSM. While the practice of conducting periodic revisions reflects an attempt to keep pace with a growing and changing understanding of the ADHD syndrome, the situation seems problematic. Subjecting children to pharmacological interventions with life-long implications and consequences should be based upon a much more solid foundation than the teacher's observations rendered in ignorance of the critical and differentiating features of ADHD (Hoggan and Dunlop, 1996). Yet that may be the usual context of such teacher evaluations which often lead to the diagnosis of ADHD and subsequent initiation of stimulant therapy.
Another facet of the current political climate is the threat that merit pay and teacher evaluations may be connected to student performance on standardized testing, while ignoring or minimizing socio-economic factors which have long been recognized to impact on such performance (Flower, 1998). A constituent perspective in this trend is the simplistic notion that teacher effectiveness is wholly or largely reflected in standardized testing. Such connections deny the uniqueness of the personal, educational and social histories of the children in question. The threat of legislative policies of this sort provide scapegoats; not accountability. Regrettably, time and space do not allow a broader discussion of these political issues, yet they are an important force in the diagnosis and treatment of ADHD. The subtle impact is to inappropriately increase pressures upon the classroom teacher, which may result in their embracing measures which will help them avoid the professional humiliation of being penalized or censured with losses in pay.
In addition to the incentives for teachers to incline their evaluations toward a diagnosis of ADHD, which are embodied in current public policies, along with those which may be in the offing, there are also disincentives which threaten to penalize teachers who do not facilitate an ADHD diagnosis. Classroom teachers are well aware of the behavioural benefits of stimulant treatment. Most may be less aware of whether a given child falls within the parameters prescribed by the DSM IV. Teachers who fail to facilitate such diagnoses may find themselves dealing with a number of behaviour problems in their classes which, in many cases, could have been avoided through participation in a process aimed at an ADHD diagnosis, regardless of the real nature of the underlying pathology. The disruptive behaviour which is often associated with ADHD can serve as a powerful inducement to teachers and parents to accept any answer, whether temporary or not. Neither are some parents likely to be pleased by a teacher who resists participation in the process if the parents in question are searching for a quick, easy means to manage their difficult child. Regardless of the various rationales offered in the medical literature, teacher participation in this process is suspect due to current incentives and disincentives previously outlined. Inadequate teacher training in the critical and differentiating features of ADHD also offers cause to be suspicious of this process. The current status quo is that we are pressured into participating in a diagnostic process about which we usually know very little.
I regret that prior to my own explorations of the scientific and teaching literature, I participated in such student evaluations. Only recently have I begun to see the hazards to children posed by this blind partnership with medical clinicians. It is a partnership which obscures issues of accountability. Each participant, whether teacher or physician, is placed beyond reproach in the current situation. Where there is an underlying pathology, the child continues to suffer the short and long-term consequences of that pathology, while the symptoms have been masked, and the problematic systemic procedures for the diagnosis of ADHD are perpetuated. This process places children at an unnecessary risk. It also provides an easy escape from responsibility to medical and teaching professionals involved in the diagnostic process.
My explorations of the literature have also convinced me that stimulant therapy offers a very effective focussing and settling agent to aid in classroom management, thus furthering the interests of the afflicted child's classmates, teachers, and the shareholders of multinational pharmaceutical manufacturers, while offering little benefit to the ADHD child.
The Child Behavior Checklist;
The Child Attention Problems Scale;
The ADHD Rating Scale;
The School Situations Questionnaire, and;
The Connors Teacher Rating Scale-Revised.
It may be of interest that in 10 years of teaching, and having participated in several evaluations of children toward the diagnosis of ADHD, and subsequent monitoring of their behaviour to determine medication effectiveness, I have never been given more than a single form to complete, which was usually a page or two in length. I have been given several copies of the same form for serial evaluations of a child's behaviour, and on another occasion, regarding a different child, I was given a single, but lengthy form to complete. My experience is very different from the process outlined by Shelton and Barkley (1990). Neither have I ever spoken with any health care professional prior to, during, or after their rendering of a diagnosis of ADHD. It is likely that such thorough methods for the diagnosis of ADHD are not as common as might be hoped. Perhaps economic considerations, in the current climate of cut-backs in education spending render such a meticulous process beyond the means of parents and school boards.
It is also important to note that this complex diagnostic process, however defensible, does not reduce the probability that an underlying food intolerance disease will go undetected. For instance, neither the medical interview nor the physical examination would be likely to identify celiac disease. It is rarely considered, and physicians are rarely knowledgeable beyond the classic symptoms which apply only to a relatively small minority of untreated celiac patients beyond infancy (Fasano, 1996). Celiac disease is the most common food intolerance disease, suggesting that milk protein intolerance, and other such diseases would be even less likely to be identified by this process.
For these and other reasons, I have pursued a greater understanding of dietary intervention therapies in ADHD. An area which holds particular promise is the exorphin hypothesis, as applied to ADHD. There is a compelling body of direct and indirect evidence in the peer reviewed scientific and medical literature, as well as in anecdotal reports, which supports the exorphin hypothesis and its application to ADHD, yet it remains a relatively obscure perspective. Implicit in the theoretical framework offered here, is also a therapeutic intervention which has had little prior application to ADHD, but which may partly or wholly alleviate this condition. This hypothesis and the attendant treatment protocol suggests the specific nature of the underlying cause of many cases of the ADHD condition, thus providing a treatment plan which offers much more than simply masking symptoms.
First postulated by Curtis Dohan, the exorphin hypothesis led to improvements among schizophrenic patients, in a clinical trial of a gluten-free, dairy-free dietary intervention (Dohan, Grassberger, Lowell, Johnson, Arbegast, 1972). Subsequent double-blind trials supported these findings (Singh & Kay, 1976; Reichelt, Sagedal, Landmark, Sangvic, Eggen, Helge, 1990; Reichelt, Ekrem, Stott, 1990). Successive investigations of the exorphin hypothesis by several groups working primarily with autistic patients have revealed information which offers to explain many otherwise contradictory findings in the literature (Hoggan 1997a). A congruent, broadly applicable set of principles inherent in the exorphin hypothesis offers to shed light on many features of a variety of mental illnesses, including ADHD, which remain obscure within the current paradigm. The exorphin hypothesis postulates an interaction between a genetic predisposition and ingestion of two very common foods, dairy products and some cereal grains (Dohan 1989). These same foods are also implicated in the two most common food intolerance diseases. This is a point of convergence which is more than coincidental. The Twentieth Century has witnessed repeated reports of clinical findings which suggest the involvement of these dietary proteins in a variety of illnesses. During World War II, Dicke observed that the cereal grains, wheat and rye, are the primary pathogen in celiac disease (Dicke, 1950). Barley was subsequently added to the list. Dicke's findings were first ignored, then mocked, and then subjected to unreasoned resistance (Hoggan 1997a). Over a period of two decades, and in the absence of any other effective treatment for this disease, Dicke's findings finally began to gain acceptance, in the context of the development of a technology which facilitated endoscopic, intestinal biopsies thus providing ostensibly objective evidence of the intestinal damage due to dietary gluten (Paulley, 1954), which supported Dicke's claims. Much greater resistance to dietary interventions in conditions which have been shown to respond to pharmaceutical intervention should therefore be anticipated, regardless of the status of the intestinal mucosa. Dietary interventions in psychiatric conditions are not currently in vogue. Worse, proponents of such interventions are often mocked, just as Dicke was (Hoggan, 1997a). Removal of the same cereals, which have been shown to be pathogenic in celiac disease, have also been shown to result in remission of symptoms of some forms of epilepsy which appear to be variants of the Sturge-Webber Syndrome (Bye, Andermann, Robitaille, Bohane, Andermann, 1993; Piatella, Zamponi, Cardinali, 1993; Tiacci, D'Alessandro, Cantisani, Piccirilli, Signorini, Pelli, Cavalletti, Castellucci, Palmeri, Battisti, Federico, 1993) some cases of a rather wide variety of neurological dysfunctions (Hadjivassiliou, Chattopadhyay, Davies-Jones, Gibson, Gruenwald, Lobo, 1997; Kelkar, Ross, Murray, 1996; Holmes, 1996; Sandyk, Brennan, 1983; Smith, Saldanha, Britton, Brown, 1997) and a number of central nervous system (CNS) ailments previously thought to be unrelated to diet (Watson, McMillan, Dickey, Biggart, Porter, 1992). These reports do not provide clear evidence that these conditions result partly or wholly from one or more of the opioid acting peptides found in the digests of wheat, rye, and barley, but the complete and partial remissions reported in the literature leave little doubt that consumption of this common food group can result in functional and morphological changes to the central and peripheral nervous systems. It should therefore not be surprising if behavioural and attentional changes also occur in response to these foods. In fact, the opposite would be surprising (Reichelt, 1996).
The exorphins derived from the aforementioned grain proteins and milk proteins are chains of amino acids called peptides, and they have been demonstrated to bind to cellular opioid receptors (Zioudrou et al. 1979). The similarity between these exogenous, opioid-acting peptides and narcotics derived from opium, such as morphine, is suggested by similarities in function and attachment at identical receptors as well as by the blockage of such binding by drugs which also block the binding, at the same receptors, of opiates (Zioudrou et al.,1979).
Exorphins act as neurotransmitters. It is possible that the comorbidity of alcoholism and ADHD (Wilens, Prince, Biederman, Spencer, Frances, 1995; Schulz, McKay, Newcorn, Vanshdeep, Gabriel, Halperin, 1998) is related, in part, to an addicting action of exogenous opioid peptides, which may lead to the reported predilection to substance abuse in ADHD (Castellanos, 1997; Schulz, et al 1998). The cortical atrophy associated with both ADHD and alcoholism (Hechtman 1993; Nasrallah et al. 1986) may also suggest the possibility of some commonalities. Work suggesting tetrahydroisoquinoline (THIQ) attachment at CNS endorphin receptors, in alcoholism, may offer a model for understanding one action of exorphins. (Bedingfield, Holloway, 1998 ).
People with learning difficulties, specifically with reading, have been reported to have an increased individual and family incidence of immune problems and auto-immune disorders, particularly those involving the gastrointestinal tract and thyroid gland (Crawford, Kaplan, Kinsbourne, 1994), which is relevant, given the very high comorbidity of ADHD and learning disabilities (Biederman, Faraone, 1996). ADHD symptoms were also reported in association with an increased familial incidence of Crohn's disease (Crawford et al.,1994) which further supports the postulated connection. The reported excess of gastrointestinal malignancies, in the context of an overall reduced incidence of malignancy among one group with learning disabilities, also becomes relevant, in that light (Cooke, 1997), as does the excess incidence of malignancy, especially in the gastrointestinal tract, in untreated celiac disease ( Hoggan, 1997b). As may be deduced from the above, there are many possible and probable causes of intestinal permeability. Undigested food particles are being absorbed into the blood of many apparently healthy people. Testing of a random population sample in Iceland revealed that 15% of this group had elevated class G immunoglobulin (IgG) antibodies against gliadin, a group of proteins found in wheat (Aarnason, Gudjonsson, Freysdottir, Jonsdottir, Valdimarsson, 1992). This is clear evidence of the inappropriate absorption under discussion, which is further supported by gluten-derived exorphins demonstrated in pancreatic secretions (Fukudome, Jinsmaa, Matsukawa, Sasaki, Yohsikawa, 1997). These findings also suggest that many and perhaps all of the same group would have exorphins in their circulatory systems, although this does not establish their presence in the central nervous system.
The general cytotoxicity of gliadin, once it has gained entry into the blood, may be the very vehicle by which the exorphins can bypass the blood brain barrier (BBB) in the context of mental illness. If there are concomitant exorphins, and gliadins in the circulation at the same time, which seems likely because they can be derived from the same foods, then the gliadins may damage the tight epithelial junctions of the BBB, thus allowing passage of the exorphins into the central nervous system. This postulation is, of course, speculative, but as previously demonstrated, the gluten-associated CNS and general tissue damage is well established. The accuracy of this speculation may not reasonably be taken to besmirch the larger thesis embodied here. The notion of cytotoxicity as a vehicle for the breach of the BBB is offered as an interesting, reasonable, and plausible possibility; nothing more.
On the other hand, in animal studies, exorphins have been demonstrated to bind to opioid receptors in the brain. It may be that either endogenous opioid peptide conservation resulting from exogenous opioids, or a direct activity of exogenous opioids upon elements of the CNS is at work, or perhaps both dynamics contribute to the etiology of gluten/dairy induced ADHD.
There is some evidence from animal studies that such apparently safe foods can result in serious pathologies. One study of cats, a carnivorous species, reports that they develop morphological CNS changes, along with behavioural changes, after regular feedings of casein and gluten (Thibault, Coulon, Roberge, 1988 ). Another study of a group of Irish Setters fed predominantly glutenous diets has resulted in villous atrophy and increased intraepithelial lymphocytes, which resolved on a gluten-free diet (Pemberton, Lobley, Holmes, Sorensen, Batt, 1997). There is also animal study evidence suggesting that these opioids may be at work in a variety of neuropathies (Schick, Schusdziarra, 1985) and mental abnormalities (Drysdale, Deacon, Lewis, Olley, Electricwala, Sherewood, 1982). Yet another study reports gluten induced autoimmunity in rats (Scott, 1996). Humans are more omnivorous than some of these animals, but there is also some human evidence suggesting that gluten-derived exorphins can and do directly impact on the human central and peripheral nervous systems (Hadjivassilliou.et al. 1996, 1997; Bye et al., 1993). A detailed discussion of this point is offered in Chapter 3. For the moment, it may be valuable to point out that there are at least 15 recurrences of one opioid-acting amino acid sequence of GYYPT which can be isolated from one molecule of gliadin, and there are a total of five amino acid sequences, with opioid activity, that have been characterized in gliadins (Fukudome & Yoshikawa, 1992). Additionally, at least eight opioid acting peptides have been identified in milk proteins (Teschemacher H, Koch G, Brantl V, 1997; Mycroft, Wei, Bernardin, Kasarda, 1982 ). This offers 13 distinct amino acid sequences, each with opioid activity, which can act singly or in concert, assuming that all can bypass the BBB, to produce a wide variety of presentations, many of which may reflect various manifestations of ADHD, as well as suggesting situational variations in presenting symptoms of ADHD. When this number is added to the repetitions of some of these sequences which occur as many as 15 times in a single molecule (Fukudome & Yoshikawa, 1993), and all the possible unique combinations of exogenous, psychoactive peptides is added to the number of endogenous peptides which may be acting individually or in concert upon opioid receptors there is a very large number of possible variations in quantity, ratio, and identity of peptides and consequent alterations to behaviour.
Of course, the increased intestinal permeability herein postulated as a feature of most cases of ADHD, along with a pathway for exorphins to pass through or exert an influence beyond the BBB, might also facilitate a similar dynamic involving a variety of other partly digested food proteins which may enter the circulation containing amino acid sequences which can exert a psychoactive influence. Thus the exorphin hypothesis does not preclude, and may offer an explanation for the reported impact of food additives and a variety of food proteins, as well as suggesting a cause for the reported variety of atopic presentations and allergies often associated with ADHD patients (Colquhoun, Bunday, 1981; Franklin1984; Breakey, 1997; Kittler, Baldwin, 1970; Aman, Mitchell, Turbott, 1987; Stevens, Deck, Abate, Watkins, Lipp, Burgess, 1995; Mitchell, Aman, Turbott, Manku, 1987; Holman, Johnson, Hatch, 1982; Stevens, Zentall, Abate, Kuczek, Burgess, 1996 ).
Further to that perspective, and assuming that the classroom teacher's primary concerns are the learning, health, and safety of students, in addition to concerns about the richness of students' futures, the uncontested follow-up reports which deny long-term benefits of stimulant therapy ( Barkley, 1977; Weiss et al., 1985; Claude et al.,1995) should herald dramatic changes to classroom teachers' involvement in the diagnostic process. Teacher resistance to blindly rendering evaluations may encourage appropriate investigation and exclusion of a variety of pathologies, as well as leading to interventions which do not involve drugging children into quiet submission. Teachers need a clear understanding of alternative perspectives, as well as the diagnostic criteria for ADHD. Such an informed approach is one reasonable means by which teachers may extricate themselves from their current and unfortunate involvement in this diagnostic process. Some constructive suggestions for altering teacher participation in this process will be postulated later. This integration of the various factors in the literature which support the exorphin hypothesis in ADHD offers teachers insight and understanding which has heretofore been unavailable to them, obscured by the parlance of medical research, and the relative inaccessibility of the literature which embodies that specialized and exclusive language. It also offers a safe and effective intervention for that part of the ADHD population afflicted by one or more of the several conditions by which exorphins alter their behaviour. Part of the journey to understanding ADHD behaviour in light of this perspective will first require that we explore the DSM IV diagnostic criteria, in relation to the activity of exorphins, which will follow in the next chapter.
According to the DSM IV, the first set of criteria for identifying ADHD are either a combination of hyperactive and impulsive behaviour, or inattention. The second criterion is that these symptoms be present and problematic prior to age seven. Third, the problematic symptoms must be present in more than one setting, which seems a reasonable means of avoiding an inaccurate diagnosis where there is a personality conflict, or some similar problem. The fourth criterion requires that these symptoms must cause "significant impairment of social, academic, or occupational functioning."
It follows that teachers are often best able to identify usual and unusual behaviour in their students, and that this is a judgement based on comparison, which does not necessarily compromise that assessment. In the interest of clarity, I will repeat that it does not follow that teachers have demonstrated competence to differentiate ADHD from other medical disorders, thus they are not competent to diagnose ADHD simply because they are arguably best able to identify children who present with unusual behaviour. Such unusual behaviour might stem from a variety of medical problems ranging from celiac disease, to hypoglycemia to abnormal thyroid function, so it is the legitimate province of the medical practitioner to differentiate ADHD from medical conditions. According to Barkley (1990) extensive differentiation of ADHD from other, similar conditions has often not received appropriate attention from the medical practitioner: "in the past such examinations have often been brief, relatively superficial, and as a result often unreliable and invalid for achieving a dianosis of ADHD or identifying comorbid behavioral, psychiatric and educational conditions." This problem may result from excessive reliance upon teachers' reports on student behaviour.
The short-term efficacy of methylphenidate is consistent with the short-sightedness of much current political thought. Reduction of governmental deficits appears to enjoy greater political popularity than the provision of adequate care to our children.
Given the economic and political climate, and in spite of the admonition in the CPS, it is all too frequently the case that teacher and medical practitioner alike facilitate stimulant therapy, without provision of additional aid for the ADHD child. Shaywitz (1988) has expressed the following concern about stimulants:
The finding that an increasing number of children are receiving stimulant medication to treat hyperactivity and inattention may reflect a regressive step in which all behavioral and learning disorders are lumped together and treated in the same way.
A patch is thus placed upon the symptoms which trouble the teacher and the problem child's classmates, but no genuine aid to the child has been rendered. Labelling a child with ADHD is of little value if only drug therapy is provided. Such practices are contrary to the recommendations in the CPS, contrary to the literature, and contrary to the best interests of the child.
Diagnosis of ADHD is most frequently driven by teacher ratings of children (Taylor, Sandberg, Thorley, Giles 1991, p.37; Haslam, Dalby, Rademaker, 1984) in the context of a process which is often initiated after one or more teachers complain about the student's behaviour (personal experience). Many of the same teachers who have complained about the child are then frequently called upon to render formal evaluations of student behaviour. These teachers are unlikely to be trained in procedures for psychiatric diagnosis, including the critical features of ADHD and the means of differentiating ADHD from other medical disorders. There is the additional risk that teachers will incorrectly identify situation-specific abnormal behaviour as consistent with ADHD (Taylor et al. 1991, p.37). Despite the DSM IV diagnostic requirement that symptoms be observed in two or more settings, teacher evaluations are given so much weight that a school-based bias may be a built-in feature of the current diagnostic process. Observations made at school alone should not, according to the DSM IV, result in a diagnosis. But the reality may be contrary to that DSM IV provision. This situation is fraught with hazards for children.
Yet the peer reviewed, medical and scientific literature harkens to the reliability and validity of assessments of students' behaviours by teachers ( DSM III; DuPaul, Rapport, Perriello, 1991; Haslam et al 1984; Martin, Welsh, McKay, Bareuther, 1984; Taylor et al. 1991). Complex rationales in support of this practice are offered in the same literature (Martin et al. 1984; DuPaul et al., 1991). One report asserts that because teacher judgements of learning disabilities are more accurate than a combination of standardized tests, that teacher evaluations are important with regard to both diagnosis and "effects of treatment on children with disruptive behaviour disorders" (Du Paul, et al., 1991). One may speculate that the very presence of such arguments in the literature is signalling a problematic relationship which has developed and which may also contribute to some of the diagnostic and long-term treatment difficulties mentioned earlier.
One of the loudest supporters of stimulant therapy is an organization known as CHADD. They gave the appearance of being an independent, non-profit, charitable group of parents with children suffering from ADHD, and adults with ADHD. An expose, last year, on the popular television news show, 20/20, revealed that much of this group's funding comes directly from Ciba Giegy, the manufacturer of the most commonly prescribed form of methylphenidate, Ritalin. Dietary interventions do not enjoy the profitability that allows for the extensive funding provided to CHADD and stimulant research. It would probably be in the best interests of such drug manufacturers to fund work aimed at discrediting dietary interventions, although I have no knowledge of such practices.
Perhaps due to our society's predilection for pharmacology, there is comparatively little published work on the exploration of dietary interventions. This may be due to the absence of economic incentives for investment in such investigations. Of course, it does not appear to be in the best interests of pharmaceutical manufacturers to invest in exploring the efficacy of dietary interventions in association with any condition, and it seems unreasonable to expect them to fund work that would undermine their sales.
Exorphins are opioid-acting peptides which derive from external sources, instead of being synthesized within the body. These exogenous opioids have been shown to bind to the same cellular receptors that endogenous opioids bind to, thus impacting on the immune system, nerve function, myelination processes, vascular walls, neuromuscular function, and a variety of CNS functions. As may be expected, such opioids can have an anaesthetizing, analgesic, and addictive effect.
Opioids, in general, have been implicated in sleep onset (Wilson, Dorosz, 1984) and hypothalmic-pituitary-adrenal axis function (Hoggan, 1997b). Reduced attention may be the result of the CNS attachment of opioid-acting exorphins. Some investigation has shown that many hyperactive children lapse quickly into sleep when they are inactive, and they often sleep very soundly. If we see deficits in attention as a possible result of opioid activity in the CNS, then the variations between urinary peptides, which have been reported to differentiate the subgroups of ADHD, may support the postulation that some of the exorphins will result in hyperactivity, while others will increase hypoactivity. Perhaps it is the variations in specific circulating opioid peptides which determine whether hyperactivity will accompany inattention, but most or all may cause the characteristic inattention in both sub-groups.
The lethargic, inattentive ADHD child, and the hyperactive ADHD child may have much in common, in that they are both under the influence of powerful anaesthetics.... ones which are similar to those used to aid people who are suffering great pain. And the positive results of stimulant therapy, in that light, may be quite understandable. Perhaps they simply function to counteract some of the gross behavioural manifestations of the exorphins. But the elimination of the source of these exorphins seems a much more sensible approach, which may serve the ADHD sufferer in two ways. It may reduce the risk of the comorbidities of ADHD, while it alleviates the debilitating, short-term symptoms of this condition.
The use of chemicals to mask the symptoms, rather than getting at the cause of such illness seems to embody a less than prudent approach to our children's health. In fact, there may be cause to see the administration of stimulant therapy as self-indulgence on the part of the adults in our culture. Pills are much easier and less costly than the initiation of in-depth medical investigations, perhaps followed by a complex dietary intervention, or some other therapy appropriate to the findings of these studies.
The four primary problems with measurement and characterization of urinary peptides in ADHD are:
The second problem may reflect cases of ADHD which result from some of the other conditions such as those postulated by Block (1997). The third problem suggests that ADHD may be located on a continuum which would include autism, schizophrenia, and some other mental illnesses. Of course, this is a political and a paradigm problem. From a political perspective, recognition of such a continuum would force increasing resources to be channelled toward a better understanding of these conditions, as there would be an increased recognition of the severity of ADHD when it is associated with such more visibly serious conditions. The paradigm difficulty associated with this problem is rooted in the arbitrary classification of illness which now dominates conventional medical wisdom, and would be challenged by recognition of such a continuum. The additionally arbitrary notion which also drives conventional medical wisdom, that most people are healthy most of the time, would fall into serious question, in light of the broad hazards to humanity posed by these two very common Western foods. Such paradigms do not change easily (Kuhn, 1970).
The fourth problem may be one of perception rather than reality. As Hole et al. (1988) point out, increased circulating exogenous peptides will inhibit the breakdown of endogenous peptides, thus reducing the overall breakdown rate of opioid-acting peptides. The exorphins may thereby have either a direct opioid-induced effect upon some parts of the CNS, or an indirect effect through the preservation of endogenous peptides, or a combination of both dynamics may contribute to the ADHD condition. Opioid-acting peptides, irrespective of origin, have been shown to induce natural sleep and sleepiness. Perhaps the folk-way use of a warm glass of milk as an aid to sleep onset may have its root in the psychoactive potential of the opioid peptides found in milk.
Of course, it is important to establish whether, as the DSM IV requires, this behaviour occurs in more than one environment. Problematic behaviours in many environments would be consistent with the exorphin hypothesis, as well as other postulations about the etiology of this disorder, but would differentiate situational problems. Contra-indicating, situational problems could arise out of personality conflicts, learning difficulties, or other issues which may not be related to, or symptomatic of ADHD, but which would be likely to occur in a single setting. The biologic effects of exorphins are unlikely to be restricted to one setting, although regular meals containing one or the other, or both dairy and cereal, for only one meal of the day could, conceivably, result in symptoms which are specific to single environments, although such a practice seems unlikely. Paul et al. (1985) have indicated that exorphins can stay in the circulation of celiac children for as long as a year after consumption of gluten. Others, however, have suggested that behavioural improvements can be seen within days of beginning a gluten-free diet (Colquhoun & Bunday, 1981).
It is clear that the DSM IV criteria would imply the attainment of 7 years of age as a precondition of diagnosis of ADHD, yet diagnosis requires the presence of some ADHD symptoms prior to that age. There is a cognitive dissonance here (Barkley, 1997) as well as the possibility that in light of the exorphin hypothesis this may be a most unfortunate feature of these criteria.
If ADHD is often the result of dietary opioids, and since cell differentiation is completed prior to that age, there may be some permanent damage which might have been reversible at an earlier age, through dietary changes. Paul, Henker, Todt, and Eyesold (1985) offer a clear argument, in this regard, for children with celiac disease. The same consideration may also apply to children with food-induced ADHD. The literature is clear that at least some cases of ADHD are food induced. The only real issue under debate is the proportion of ADHD children whose diet is partially or totally resulting in their problems.
The requirement that symptoms appear prior to age 7 has come under attack from other directions. Barkley and Biederman (1997) have stated:No support exists for the selection of age 7 years for onset of a valid disorder, either for symptom onset or for onset of impairment.
Another group indicated that many diagnoses of ADHD primarily characterized by inattention would be missed if the age of onset was blindly accepted (Applegate, Lahey, Hart, Biederman, Hynd, Barkley, Ollendick, Frik, Greenhill, McBurnett, Newcorn, Kerdyk, Garfinkle, Waldman, Shaffer, 1997). On one hand, I am asking that less attention be paid to the age-of-onset criterion, while I have previously argued for increased attention to the differentiation of ADHD from other pathologies which can be identified via standard blood tests.
Considerable overlap between ADHD children, and those with untreated celiac disease also exists in the frequency with which their condition interferes with their social, academic, or occupational function. Many celiac children are withdrawn, emotionally volatile, argumentative, and resistant to direction, as are many children afflicted by ADHD. It must be conceded that such unpleasant behaviours may also present in a variety of other conditions, and celiac disease is offered as a model for behavioural impact of exogenous opioids, and certainly not as a blanket diagnosis of all cases of ADHD.
Since there are five known types of opioids which have been isolated from proteins in wheat, and eight which have been isolated from milk proteins the number of possible variations in presentations should amount to the square of the sum of these two numbers. This computation ignores variations which may arise from variations in immune responses, quantities consumed, as well as other partly digested food particles and a variety of food additives which may be entering the blood via the route prepared by drugs, infection, or food-induced intestinal permeability which will be discussed at length in a subsequent chapter. It is clear that the variety of possible presentations of ADHD, if exogenous peptides are an etiologic factor in this syndrome, is very large indeed. Differentiation of ADHD can be a difficult task, and the Exorphin hypothesis offers a very good explanation for this difficulty, as well as offering strong inducement for including both milk protein intolerance and gluten intolerance in the differential diagnosis of ADHD.
Failure to differentiate these conditions may lead, by default, to children being denied treatment of another condition which may have some very serious, life-threatening and debilitating sequelae. The administration of stimulants without first excluding gluten intolerance, can lead to a very high risk of a variety of malignancies (Hoggan, 1997b) but it can also lead to epilepsy, crippling neurological disease, and serious skeletal and articular maladies, all of which may have been averted by accurate diagnosis, and appropriate treatment.
The first is about Lewen, a young fellow who did not mount a discernable IgA or IgG immune response to gluten, but who has experienced great benefits from the gluten-free diet. This is one problem with seeking evidence of immune responses against gliadins or casein. Some people who have an intolerance to these proteins do not seem to mount an immune response of the sort identified in gluten sensitivity by current testing methods. These folks do not have celiac disease, but they are clearly intolerant, as is witnessed by changes in their behaviour during dietary exclusion of gluten and dairy products. Most, including the patients themselves, would agree that the changes are large improvements.
The reverse of Lewen's situation was also reported in a magazine article which has been submitted for publication (Hoggan & Fasano, 1998). The principles have chosen to remain anonymous to avoid further victimizing a young man who has already paid too great a price for the medical profession's failure to diagnose his celiac disease at a much earlier date. The article chronicles the various diagnoses and events which eventually led to his commitment to a mental hospital. It does little to recount the emotional anguish he and his parents suffered. Therapists joined with other health care professionals who attended their son, and chastised the parents for their poor parenting skills. It is quite conceivable that this young man could have languished for most of his life in a series of institutions until he eventually succumbed to one of the deadly sequelae of celiac disease. He was diagnosed with ADHD at an early point in his life. Consistent with the dramatic rates of under-diagnosis of celiac disease, he was labelled as having this psychiatric disorder without ever having been tested for food intolerances.
In spite of many allergies, a slight build, difficulty swallowing, and abdominal distress, this young man was never investigated for celiac disease until after he had very nearly been killed by the combination of pharmaceuticals he was given to deal with his allergies and his psychiatric symptoms. It is amazing that we continue to listen more carefully to apparently objective claims, to the exclusion of simple symptom reports from children. This young fellow's dismissal was tantamount to denying his voice. He was silenced on the issue of his own health, and almost died because of that muting process. Perhaps the lesson it teaches is that we need to genuinely listen to children.
Appendix two is a summary of examples of gluten-induced anger in the children of people with celiac disease. It is written by Carol, who has celiac disease herself, yet she missed the possibility in her own child. Responses from other parents have motivated her to have the child tested for celiac disease. This anger and aggressive behaviour may well be similar to that demonstrated in many ADHD children, perhaps arising out of similar causes. Anyone who is knowledgeable in the realm of celiac disease and gluten-induced behavioural abnormalities will recognize the characteristic, violent, irrational anger.
These accounts offer an interesting perspective on ADHD and a compelling connection with gluten. It would appear that the gluten, and perhaps the derivative exorphins were at the root of the attentional and behavioural symptoms recounted in these anecdotes.
I have seen accounts of similar reactions to dairy products. There may be other foods that warrant investigation as well. Perhaps the most salient issue here is that humanity has only consumed these foods for a very short period, in evolutionary terms. Although gluten-containing grains have been cultivated for 10,000 years, and dairy products have been consumed for 5,000 years, some cultures have been consuming them for only a few decades, while others for only a few centuries. That is a very short time, and is probably insufficient for adaptation, especially since the many of the more lethal sequelae may not develop until well after puberty, and hence reproductive capacity.
Appendix four is a discussion of some of the health problems associated with early cultures adapting to cereals. Given the rates of both autoimmunity and ADHD among indigenous Amerindian populations, there may be more value to a more traditional diet for these folks than the celebration of their traditional culture. There may be some genuine health benefits. The incidence of type II diabetes in these hereditary groups, as was discussed earlier, certainly supports the notion that a more traditional diet may lead to improved physical and mental health, as well as improving academic prospects in this group.
Vilhjalmur Stefansson (1960) has suggested a link between health problems among North American Natives, and the Western diet. He did not identify gluten or dairy products as specifically problematic, but these may well be the elements of the European diet that caused the problems Stefansson observed and reported.
Most of the industrial world is now consuming large quantities of gluten-containing grains. These grains have been demonstrated to compromise absorption of calcium and other minerals in everyone consuming them. For a significant minority of the population, a host of health problems accompany the consumption of these grains. There is a great deal of evidence suggesting that gluten may also contribute to the rapidly increasing incidence of malignancy. Gluten has been implicated in the pathogenesis of schizophrenia, bi-polar disorder, obsessive-compulsive disorder, and autism (Dohan et al., 1969; Singh & Kay, 1976; Reichelt, et al, 1990a). It does seems very reasonable to suggest that it may also be involved in ADHD. In the absence of a positive response to the exclusion of known sources of exorphins, there is some cause to favour stimulant therapy. ADHD children often suffer socially because of their behavioural limitations. Stimulants may help a child to avert serious injury to both self-esteem and social development, through allowing the student to "fit in" with peers.
Interference with classmates' learning may also lead to social difficulties for the child, and such interference is less likely during stimulant therapy, but this does not obviate the need to differentiate ADHD from food intolerance disease prior to considering stimulants.
Appendix five offers a description of one person's experience with stimulant therapy, when the underlying pathology was gluten intolerance. The stimulant was a very effective tool for calming this boy. What he really needed, however, was a conscientious physician to explore the other possible causes of his learning and behaviour problems, including the possibility of food intolerance disease. An understanding of the identification and action of exorphins could also have contributed to the child's well being, but that research had not yet been done when he was in school.
The application of the exorphin hypothesis suggests what is probably the least complicated explanation of the greatest number of features of ADHD. Hypoarousal, in some regions of the brain, has long been recognized as a feature of ADHD. The possibility that there is a narcotic effect from opioid peptides is very consistent with such reduced arousal, with comorbid learning disabilities, and with the DSM IV observation that ADHD children " often appear as if their mind is elsewhere or as if they are not listening or did not hear what has just been said (Criterion A1c)." The elevated incidence of atopy in ADHD (Boris & Mandel, 1994; Breakey, 1997) is both parallelled by a similar incidence in food intolerance disease, and is quite possibly the result of immune system abnormalities in response either to foreign peptides, or nutrient deficiencies, which are reported in association with celiac disease, other enteropathies, and ADHD. Increased opioid activity in atopic skin disorders may be implicated through autoimmunity (Scott, 1996). Delayed myelination and delayed CNS development, along with abnormalities in myelin, CNS, and neurotransmitters are also reported in connection with both ADHD and celiac disease. Opioids have been implicated, in animal studies, in delaying neuron and glial development (Zagon, McLaughlin, 1990) dendrite development (Hauser, McLaughlin, Zagon, 1989), and brain development (Zagon, McLaughlin, 1984). Additionally, abnormalities in mood and behaviour, are also reported in food intolerance disease and are a defining characteristic of ADHD, as was mentioned earlier.
Each of these points of convergence have been reported in the medical literature as significantly connected with ADHD, food intolerance disease, and opioid or opiate activity. The challenge is to bring together all the disparate evidence in a cohesive and cogent manner. Examination of the complex web of evidence that exorphins are a large factor in a majority of cases of ADHD, if duly presented here, seems likely to sway even the most skeptical reader to consider the exorphin hypothesis in ADHD. This hypothesis provides possible explanations for variations in severity, various presentations, and many of the wide array of comorbidities. To further this discussion, it will be necessary to engage in a more detailed exploration of peptide structure, intestinal permeability, and food protein intolerance diseases. It will also be valuable to explore the double-blind trials which first suggested the existence of exorphins, the functional similarity of exorphins to morphine, the role of opioids in essential fatty acid metabolism, opioid-related alterations to the immune system, brain development and perfusion, abnormalities in the neurotransmitters, serotonin and dopamine, mineral deficiencies, and finally, how these factors may underlay the various signs and symptoms of ADHD.
While we are currently aware of about twenty amino acids, there is a vast number of proteins and peptides. Proteins are complex structures, the details of which are beyond the scope of this discussion. It will be sufficient to recognize that proteins can and do differ quite dramatically from each other, both on the basis of constituent amino acids, and the specific sequence of these amino acids in the primary structure of the protein.
Imagine a language where there are twenty letters in the alphabet, and word length can vary from two letters, as in a dipeptide (Tortora & Grabowski 1996), to 800 letters, as in the primary structure of high molecular weight glutenin (Fukudome & Yoshikawa 1992) and other proteins with even more complex structures can exceed 2,000 amino acids (Beaver, 1998). This suggests an almost infinite number of possible combinations in peptides and proteins of distinct structures. That is the language of peptides and proteins.
It is a language that speaks directly to the human digestion process, which cleaves the peptide bonds in dietary proteins, through a variety of mechanical and chemical processes, ultimately degrading these proteins to constituent amino acids which can then be absorbed through the intestinal wall, and into the circulation as nutrients. In addition to the provision of water, acids, and mechanical insult, to facilitate this liberation of amino acids from the proteins of which they are constituents, the gastrointestinal tract must provide catalysts to speed the chemical cleavage of these peptide bonds, in the breakdown of dietary protein. In the absence of such catalysts, the process would be impossibly slow (Tortora & Grabowski, 1996).
Digestive enzymes serve as such catalysts. Beginning with salivary excretions in the mouth, our food is exposed to a very wide variety of enzymes as it makes its passage through us. These enzymes often target particular covalent bonds. Thus, the absence or reduced quantity of specific enzymes may herald the survival of some of these peptide bonds, and herein lies one of the preconditions for exorphins to act as etiologic factors in ADHD.
The exorphins are peptides which result from incomplete digestion of proteins, and by themselves may lack significance. However, when such products of enzymatic deficiency are coupled with intestinal permeability, there is a host of problems which may be in the offing, when consuming a modern, Western diet, including ADHD. If these peptides are allowed to enter the circulation, they can act upon the body in ways similar to narcotics, and/or endogenous opioid peptides.
Even where there are adequate digestive enzymes, it seems reasonable to suggest that increased intestinal permeability may result in the absorption of a small number of exorphins which would otherwise have remained in the intestinal lumen for further digestion.
Passage of whole and partly digested proteins has been established even in healthy subjects (Husby et al., 1985 ). Zioudrou et al. (1979) have identified some opioid peptides in the digests of wheat prolamines and dairy proteins which have opioid activity, and Fukudome and Yoshikawa (1992) have since characterized 15 separate amino acid sequences of gluten-exorphin A-5 in a single molecule of wheat. It would be surprising if there were not some quantity of these psychoactive peptides entering the blood of a significant number of people consuming a Western diet . It bears noting that four other opioid-acting amino acid sequences have also been identified in wheat protein and may also occur in multiple regions of the proteins in this very common food ( Fukudome & Yoshikawa, 1992). It is thus clear that the exorphins which are herein postulated as underlying ADHD can be derived from the incomplete digests of alcohol soluble proteins found in the common cereal grains: wheat; rye; barley; and perhaps oats, as well as from the incomplete digests of dairy products. It is also likely that passage of at least some of these exorphins into the blood, as is witnessed by anti-gliadin antibodies, is occurring in at least 15% of the random population mentioned earlier (Arnason, et al., 1992). There is also a significant population of patients with autism, schizophrenia, and bi-polar disorder, many of whom do not mount a discernable antibody response to these proteins, but whose symptoms improve on a diet which excludes them (Reichelt, 1996).
One sequence of amino acids which has been identified in abundant quantity in both wheat and cow's milk is similar to melanocyte-stimulating-hormone-release-inhibiting factor (MIF) which has been shown to enhance CNS dopaminergic activity in animals (Mycroft et al,1982). A condition of increased central dopaminergic activity has long been associated with ADHD and a variety of other psychiatric conditions (Gill, Daly, Heron, Hawi, Fitzgerald, 1997; Raskin, Shaywitz, Shaywitz, Anderson, Cohen, 1984).
The earliest report that opioid peptides could be derived from food proteins is probably that of Zioudrou et al.(1979). This group named exorphins and established their functional similarity to morphine. They reported that Naloxone, a morphine antagonist, blocked 70% of gluten-derived exorphin activity, while blocking 100% of milk-derived exorphin activity. Animal studies conducted by the same group show that these exorphins will bind to opiate receptors in the brain. Gluten-derived opioids are thought to have a much greater potency than those derived from milk, and the former are claimed to have a potency that is a small fraction of that of morphine (Huebner, Lieberman, Rubino, Wall, 1984), so the signs of behavioural impact would likely be much more subtle than is seen in morphine addiction.
Recognition of gluten and dairy products as the source of such dangerous peptides is relatively new. There was evidence almost thirty years ago, from double blind trials that some schizophrenics benefited from exclusion of gluten and dairy from their diets (Dohan, et al, 1969; Singh & Kay, 1976). Apparently no other information was then available to explain the postulated pathogenic nature of these foods.
The earliest report was from Dohan et al. (1969). A total of 102 patients, on a locked ward, participated and everyone in the experimental group showed improvement which apparently resulted from the dietary intervention. The patients in question were released earlier than previous patients who had consumed a regular diet These positive results were replicated by all the researchers who worked within the clear and simple parameters outlined by Dohan. It was a decade after publication of the first clinical trial of this diet with schizophrenics, that Zioudrou et al. (1979) published their discovery of morphine-like peptides in the digests of wheat and dairy products, thus providing subsequent support for the application of the exorphin hypothesis to schizophrenia.
The identification and characterization of these exorphins followed some problematic attempts to replicate the early trials which had implicated these foods in the pathogenesis of schizophrenia. Davis (1978) and Vlissides, Venulet, Jenner (1986) and others attempted to test the therapeutic value of gluten-free diets in schizophrenics. Each failed to comply with the original investigative methodology established by Dohan et al. (1969) in several important features of their work. Vlissides et al. (1986) chose to test chronic schizophrenics and other chronic patients with distinct mental disorders, who had a mean duration of hospitalization of more than 4 years. This is a group which Dohan (1972) had expressly indicated that he had little hope would benefit from the dietary protocol he and his group had pioneered. Vlissides et al. (1986) also failed to exclude milk from the experimental diet and they allowed relatives to bring gifts of food, after providing a list of gluten-containing foods to avoid. Anyone who mounts a fairly significant and rapid response to gluten, and has therefore followed a strict gluten-free diet can explain the weakness in this approach. Dietary compliance is an intense learning experience. Errors are the rule, not the exception, as one learns the pitfalls of such a diet in the context of a culture inundated with gluten. The expectation that relatives could master such a diet from a list is, at best, foolish. This practice may be very revealing of the care that was taken with the diet within the hospital. I find it astounding that there were any improvements, but Vlissides et al.(1986) reported some marginal improvements among their chronic patients, which did not reach statistical significance.
Similarly, Davis chose trial periods of comparatively short duration, of six weeks, and included milk. It was, in fact, used as a medium for administering the placebo and/or the gluten in the context of a double-blind trial. It also appears that Davis expected the patients to manage their own compliance with the diet, on the basis of a posted copy of "the Coeliac Society's handbook of acceptable and non-acceptable food and drink". Wheat starch, which was listed as acceptable by that society, has since been shown to cause symptoms in a large majority of celiac patients studied (Chartrand, Russo, Duhaime, Seidman, 1997). The net result was that these flawed studies undermined the solid results of much more defensible methodologies employed by Dohan, et al, (1969); Singh & Kay (1974); Reichelt (1997) and others, who had achieved positive results. The casual attitude toward diet, as reflected in the published reports of Vlissides et al.(1986) and Davis (1978) would predict their equivocal and negative results, yet theirs was the work that held sway.
This scenario may lead us to question why scientists would have blithely accepted the results of the weaker studies as legitimate refutations of the earlier, more meticulous work. Thomas Kuhn (1970) has addressed a similar question about scientists' observations, by citing two experiments which offer insight into the current question. Both reports show that human subjects sometimes see what they expect to see. The first experiment he cited was conducted by Bruner and Postman. They flashed playing cards to their subjects, a few of which had been altered to either black or red, the opposite of the usual colour for that suit. Subjects quickly identified the usual playing cards correctly, but they identified anomalous cards as either belonging to the correct suit, based upon the shape of the icons, or the suit which would be correct for that colour. Hesitation and doubt only arose when the subjects were exposed to the anomalous cards for lengthier periods of time. In other words, unless forced to study the issue, they saw what they expected to see, and neatly fitted it into their current schema. In another, similar experiment cited by Kuhn, subjects were given eye glasses which turned their vision up-side-down. The subjects quickly adapted to these lenses. Again, the notion that we see what we expect to see was supported. I suggest that in the absence of the later work demonstrating opioid peptides in these common foods, members of the scientific community saw what they expected to see when they read refutations of the therapeutic benefits of the gluten-free, dairy-free diet in schizophrenia.
Consequently, the early work of Dohan et al.(1969) Singh and Kay (1976), and others had been dismissed as one of the many "blind alleys" which are common to science, and which are well recognized as valuable because they exclude fruitless avenues for scientists who will follow. Thus, the subsequent evidence from Mycroft et al. (1982), Fukudome & Yoshikawa (1992), and Zioudrou et al (1979), about cereals and milk as sources of psychoactive peptides, had little impact upon the thinking of researchers investigating schizophrenia and other mental illnesses. To most, it was a closed issue. Perhaps the later work revealing exorphins in these foods was interpreted as an attempt to shore up a faltering hypothesis. Fortunately, a few researchers have continued to recognize the importance of those clinical trials and the subsequent findings about the constitution of these food-derived exorphins. These latter few investigators have pressed forward.
Dohan's predilection for mystery stories may have served him well. He knew he had come upon some very important clues to understanding schizophrenia.. He continued this work to the end of his life.
"'The day before he died, we got a paper from a scientist in Norway, Evidence and Arguments for Schizophrenia as a Dietary Disease and it was the last thing I read to him' said his wife Marie. That night, she got as far as Page 5. He died the following morning." (Philadelphia Inquirer, Nov 14, 1991) (Ronan, 1995).
Dohan had experienced considerable frustration as he tried to disseminate his findings. His work challenged conventional medical wisdom in an important way. He was suggesting that a food which had been consumed by humankind for as long as 10,000 years, was pathogenic to perhaps as much as 2% of the world's population. If Dohan's claims were supported, many of the dietary recommendations offered by many physicians throughout much of the Twentieth Century might be seen as arising out of consensus, rather than scientific thought. Dohan's ideas were not well received. Still, there is a recent article suggesting an immunological connection between ADHD and schizophrenia (Holden, Pakula, 1995).
It is also interesting that a report published in November of 1997 identified reduced perfusion of the frontal cortex, measured by photon emission computed tomography, in connection with schizophrenia. It is even more interesting that the patient in question was subsequently diagnosed with celiac disease, and following institution of a gluten-free diet, the psychiatric symptoms resolved and there was a normalization of blood flow to the frontal cortex (De Santis, Addolorato, Romito, Caputo, Giordano, Gambassi, Taranto, Manna, Gasbarrini, 1997). Such technological advances threaten to discredit the current medical paradigm, but history continues to repeat itself as resistance to new ideas continues to be very strong, and succumbs only to very compelling evidence.
Institution of Dohan's dietary interventions was a clear outgrowth of Dicke's discovery of the therapeutic value of a gluten-free diet in the treatment of celiac disease, which was the first effective treatment to be found for an illness that had been characterized as much as 2,000 years earlier (Cooke & Holmes, 1984). This disease had a childhood death rate which was reported, more than a century ago, in as much as 75% of one physician's experience (Gibbons, 1889).
Celiac disease and other food intolerance diseases offer a window of insight into the possibility that exorphins are pathogenic in ADHD as well as a variety of psychiatric illnesses, but such a hypothesis may be subjected to vigorous resistance, just as Dicke's and Dohan's work was dismissed and mocked (Hoggan,1997a). Celiac disease is grossly under-diagnosed, and many people fall prey to malignancies that could have been prevented (Hoggan, 1997b). The gluten and dairy-free diet has even been shown to have therapeutic value in the treatment of malignancy (Donaldson, Jundt, Ricour, Sarrazin, Lemerle, Schweisgtuth, 1975; Reading & Meillon, 1984; Donaldson, 1977).
Early descriptions of celiac children characterize them as whiny, impulsive, attention seeking, sometimes angry, and a behavioral challenge to their caretakers (Colquhoun & Bunday, 1981). Some of these children are hyperactive or given to violent temper tantrums (appendix 2) others are lethargic. This description may also be applied to most of those people who have been diagnosed with ADHD. Anger and defiance are features often reported in untreated celiac patients. Additionally, celiac disease is a condition where there is an overwhelming body of evidence supporting the involvement of exorphins. Increased intestinal permeability is a well recognized feature of this disease, and Paul et al. (1985) have stated that when celiac children ingest gluten, there is a dose-dependent severity of EEG abnormalities. Kozlowska (1991) has asserted that these abnormalities are the same as those found in ADHD.
Short stature is another point of convergence between ADHD (Spencer, Biederman, Harding, O'Donnell, Faraone, Wilens, 1996) and celiac disease (Arruchio, et al., 1988). Celiac disease is primarily seen as a bowel disease which is variously characterized by chronic constipation and/or diarrhea (Fasano, 1996). ADHD has also been associated with chronic constipation (Snow, 1975) and with chronic diarrhea (Kalm 1983). Although not usually seen as a critical feature of celiac disease, increased intestinal permeability is a consistent feature of this condition (Arranz, Bode, Kingstone, Ferguson, 1994; Holm, Savilahti, Koskimies, Lipsanen, Maki, 1994). The presence of IgG class antibodies against gliadin, one of the alcohol soluble protein groups in wheat, in virtually all untreated celiacs, is one more indication of increased intestinal permeability in this condition. These antibodies may also be found in the circulation of many who suffer with other conditions, but they are found in the sera of most untreated celiac patients (appendix seven). The association of increased intestinal permeability with untreated celiac disease is so well accepted that the more economic testing for such permeability has sometimes been used to screen for celiac disease (Smecuol, Vazquez, Kogan, Cabanne, Niveloni, Pedreira, Boerr, Maurino, Meddings, 1997; Vogelsang, Genser, Wyatt, Lochs, Ferenci, Granditsch, Penner, 1995), although there are critics of such methods who assert that such screening misses the milder cases of celiac disease (Catassi, Fabiani, Ratsch, Bonucci, Dotti, Coppa, Giorgi, 1997). This permeability may explain the increased incidence of atopy commonly reported in celiac patients (Kitts, Yuan, Joneja, Scott, Szilagyi, Amiot, Zarkadas, 1997; Stevens, Connolly, Murray, McCarthy, 1990; Reading, Watson, Platt, Bird, 1971; Sandyk, Brennan, 1983). It may also offer insight into similar comorbidities among ADHD subjects (Biederman, Milberger, Faraone, Guite, Warburton, 1994; Breakey, 1997; Mitchell, et al. 1987; Stevens, et al. 1995; Aman, et al. 1987; Stevens, et al. 1996).
There is evidence independent of the ADHD literature that atopy such as recurrent serous otitis media should be investigated for dietary allergens (Nsouli, et al, 1994). Despite a wealth of reports of increased inner ear infections in ADHD, the possibility of food intolerance is ignored by many of these investigators.
If one can accept the possibility of increased permeability which is similar although usually not identical to that found in celiac disease and other food intolerance disease, as a feature of many cases of ADHD, the next step is to establish the likelihood that incompletely digested peptides, exorphins, may be over-represented in the ADHD subject's gut, leading to transport of significant quantities of exorphins into the blood.
If these enzymatic deficiencies are genetically coded, and if they are significantly associated with HLA B8, there may be cause to believe that a large percentage of our children who are afflicted with ADHD, which also appears to be influenced by genetic factors, fall into the genetic category which codes for HLA B8. If that is the case, then a failure to cleave the peptide bonds within some of the exorphins, in combination with increased intestinal permeability, may lead to absorption of these macromolecular exorphins into the blood of ADHD sufferers. Although speculative, confirmation may result in changes to current perspectives on many mental illnesses, including ADHD. It is a scenario which is possible. Questions of relative risk are not answerable until the connections are investigated but there is some interesting data which support such a genetic possibility. Kaczmarski, Kurzatkowska (1988) have reported a very high familial incidence of cow's milk intolerance in the families (34%) of children with cow's milk intolerance, and a 13.3% family incidence of gluten intolerance was revealed in the families of children with celiac disease. There appears to be a very strong familial pattern of food intolerance, which may also include patterns of digestive enzyme deficiencies. Similar familial patterns have also been observed regarding ADHD patients (Biederman, Faraone, Keenan, 1992; Sandberg, 1996; Hechtman, 1996). Investigation of ADHD subjects for deficiencies of digestive enzymes may thereby be very revealing.
Investigations of children of short stature has revealed that 5% to 20% of these children have celiac disease (Arucchio, et al, 1988). Growth deficits in ADHD subjects have recently been reported to be independent of the stimulant therapy, although these drugs had previously been blamed for this problem, thus illuminating yet another connection between the two conditions.
The relative risk of malignancy is so dramatically greater among untreated celiac patients, that regardless of whether the exorphin hypothesis proves to be applicable to ADHD, it is a matter of some urgency to accurately affirm or deny the possibility. Rapidly increasing numbers of children who are diagnosed with ADHD may predict an explosion in malignancy rates, especially lymphomas and gastrointestinal adenocarcinomas. If action is not soon taken and the possibility of frequent, underlying dietary intolerance disease is either refuted or supported, our neglect of this issue may incur a huge hidden cost.
It is important to note that a deficiency state, not a total absence of such enzymes, would be a sufficient pre-condition of the postulation hypothesized above. Neither would the genetic coding for enzymatic deficiencies constitute a critical feature of the application of the exorphin hypothesis to ADHD. The foregoing is purely speculative, but the evidence of atopy, food allergies, food intolerances, and similar EEG abnormalities in both celiac disease and ADHD is compelling. This evidence suggests both increased intestinal permeability, and perhaps, enzymatic deficiency in both ADHD and celiac disease. The genetic, atopic, and dietary factors which have been identified in celiac disease and ADHD have offered the opportunity for such speculation, but this should not be construed as a critical feature of the central argument of this discussion.
Neither should the above comments be taken to suggest that ADHD and celiac disease are the same condition. Although there is strong evidence of considerable overlap of the symptoms of both conditions, and there may be many cases of untreated celiac disease among those suffering from ADHD (see appendix five), it is clear that the ADHD group constitutes a much larger segment of the population.
It may once have been defensible to overlook celiac disease in the differential diagnosis of ADHD. Celiac disease was previously thought to be rare. New research (Not et al. 1997) however, has revealed an incidence of about 1:250 among healthy American blood donors, and approximately the same incidence among Italian school children (Catassi, et al., 1996). Occult celiac disease may well constitute a significant portion of ADHD. Undiagnosed cases of milk protein intolerance, and other protein intolerance diseases may also comprise a significant percentage of ADHD cases. There is also some evidence suggesting that intestinal permeability is a feature of most cases of ADHD which will be discussed shortly. For now, it might be valuable to examine the rates of intestinal permeability that have already been reported in the literature.
The same population of healthy blood donors who showed a 1:250 incidence of celiac disease, demonstrated an incidence of antibodies against gliadin in 4.75% of the subjects suggesting at least a seventeen fold increase of intestinal permeability compared to the incidence of celiac disease, but this is in a select population of blood donors. Those with anaemia, and other such conditions which are much more common in food intolerances, would be excluded from giving blood. Testing a random population would be much more informative. An examination of a random population in Iceland revealed that 15% of those tested demonstrated elevated antibodies against gliadin, suggesting that 15% of the general population may have increased intestinal permeability. A majority of these folks are not likely to have celiac disease, but the antibodies indicate that they are mounting an immune response to the most common food in our Western diet These antibodies imply that macromolecules of dietary proteins are entering the circulation of at least 15% of the general population, many of whom are deemed to be healthy. While most of these folks probably do not have celiac disease, some features of gluten intolerance may be present, and may offer important insights into ADHD.
Psychotic incidents have been reported in ADHD (Pine et al. 1993), which are responsive to stimulant therapy. These incidents include hallucination and delusions, symptoms which are consistent with, but not exclusive to schizophrenia, bi-polar disorder, and autism. Many of the symptoms described by Shannon (1922) in what was, perhaps, the earliest report of the treatment of ADHD symptoms with dietary exclusion, are symptoms found in ADHD patients, celiac patients, and in a variety of mental disorders which may be implicated in the Exorphin hypothesis. Shannon described these children as neurotic. Similar psychiatric symptoms are reported in more than 70% of celiac children (Kozlowska, 1991).
Comorbidities in ADHD include language and learning problems reported at 32% and 74% respectively (Mitchell, et al. 1986) . It is of more than passing interest that progressive aphasia and dysarthria have been reported in some cases of untreated celiac disease (Skully, Maark, McNeely, McNeely, 1988). In such cases, language competence usually improves following institution of a gluten-free diet In celiac disease, we may deduce the possibility that exorphins were somehow involved in the interference with language competence. Of course, other factors in celiac disease may, partly or wholly, be the cause of such language and learning problems. Nonetheless, the possibility of exorphin involvement seems quite arguable. The same also seems possible in the large number of cases of ADHD, where there are comorbid language learning problems ( Mitchell et al., 1986; Biederman et al. 1996).
The concept of molecular mimicry arises out of a theoretical perspective which has been supported in several important research venues. This concept is currently enjoying increasing attention, if the volume of publications on this subject can be taken as reflecting such an increase ( Medline search, March, 1998). The molecular mimicry perspective argues that the incursion of polypeptides into the circulation leads to selective antibody production. These antibodies are sensitized to specific amino acid sequences present in the invading peptide or in a combination of the invading peptide and tissues to which they have bound. If similar amino acid sequences are present in protein structures within body tissues, the same antibodies may attack these self cells, resulting in autoimmune damage to the tissues in question (Tuckova, Tlaskalova-Hogenova, Farre, Karska, Rossmann, Kolinska, Kocna, 1995; Oldstone, 1987).
The invading peptides, if derived from a common food which is usually consumed on a daily basis, such as dairy products or gluten, may thereby incite autoimmunity and perpetuate it as long as such dietary practices continue. This, of course, would apply to many of the autoimmune conditions which have been associated with celiac disease, including neuropathies. It may also apply to neuropathic and other autoimmune conditions which are often found in ADHD, some of which may have suggested the earlier name for this condition: "minimal brain damage" (Mitchell et al., 1987).
Delayed myelination and delayed development of CNS morphology have also been suggested as features of ADHD (Castellanos, 1997; Castellanos, Giedd, Rappoport, 1994; Hynd, Semrud-Clikeman, Lorys, Novey, Eliopulos, 1990; Semrud-Clikeman, et al. 1994; Ucles, Lorente, Rosa, 1996). These are also consistent with the concept of molecular mimicry resulting from increased intestinal permeability, combined with consumption of cereals and/or dairy products. Delays in neuron, glia, dendrite, and brain development have also been associated with opioid peptides (Hauser, et al., 1989; Zagon, et al., 1991; Zagon, et al., 1984).
Another autoimmune condition, thyroiditis is an ailment which is commonly associated with both ADHD and food intolerance disease. Brucker-Davis, Skarulis, Grace,, Benichou, Hauser, Wiggs, Weintraub, (1995) report a 60% incidence of ADHD among persons with resistance to thyroid hormone. Another group reports a 5.4 % incidence of thyroid abnormalities in ADHD, as compared to an incidence of less than 1% in the general population (Weiss, Stein, Trommer, Fefetoff, 1993). Freeman (1995), Counsell, Taha, Ruddell, (1994) and Collin, Salmi, Hallstrom, Reunala, Pasternack, (1994) all report an increased coincidence of autoimmune thyroiditis in association with celiac disease.
Hypoperfusion, of some parts of the brain, has been reported in ADHD (Castellanos, et al., 1994) and celiac disease (De Santis, et al. 1997). Cerebrovascular disorders have long been identified in celiac disease ( Rush, Inman, Bernstein, Carlen, Resch, 1977). The possibility of a connection seems worthy of investigation. The cortical atrophy reported in long term follow up studies of subjects who experienced lengthy periods of stimulant therapy as youngsters may be the result of reductions in blood supply as a function of their ADHD condition, rather than a deleterious result of either stimulant therapy, or substance abuse. Alterations to vascular health and dilation may result from the same underlying cause in both celiac disease and ADHD. In keeping with the exorphin hypothesis, an increased risk of cerebral vasculitis has also been reported in legal and illegal uses of opiate drugs (Brust, 1997).
Metabolically active areas of the brain command a greater portion of available circulation (Zeisel, 1986) which would suggest reduced nutritive supply to those areas which are less active, as may be inferred in regional hypoarousal. Celiac disease has also been demonstrated to exert an important effect upon vascular dilation (Rush, et al. 1977; Bye, Andermann, Robitaille, Bohane, Andermann, 1993; Tiacci, D'Alessandro, Cantisani, Piccirilli, Signorini, Pelli, Cavalletti, Castellucci, Palmeri, Battisti, Federico, 1993; Rush , Inman , Bernstein , Carlen , Resch, 1986) ) so it may be reasonable to suspect that the reduced blood supply may result from the action of exorphins upon vascular walls in some regions of the brain.
This may also support the perspective suggesting a reduced state of arousal in some regions of the brain, as lowered glucose metabolism has been reported in "medial frontal, parietal, and occipital areas"(Semrud-CIikeman M, Filipek P, Biederman J, Steingard R, Kennedy D, Renshaw P, Bekken K, 1994). Additionally, according to Castellanos et al.(1994): "Functional imaging techniques used to pinpoint the specific anatomic substrates of ADHD have implicated striatial hypoperfusion and low global glucose metabolism, particularly in frontal regions" (Castellanos et al., 1994).
Altered brain morphology in ADHD supports the perspective that the problem is "rooted in the processes of the cerebral cortex and some subcortical structures" (Levy, Ward, 1995). This information may prove valuable to future diagnosticians. Therapeutic interventions in nutrient delivery to neglected parts of the brain in ADHD may already be a feature of one type of intervention. Levy reports that " hypoperfusion of the caudate and central frontal lobes, accompanied by relatively hyper-perfused occipital lobes tended to be reversed by methylphenidate" (Levy, Ward, 1995). Neuromuscular disorders have recently been reported as the presenting feature of some cases of celiac disease (Hadjivassiliou et al., 1996, 1997; Cooke & Holmes 1984). Perhaps similar problems may also have significance in the increased awkwardness reported in ADHD (Kinsbourne, 1975). In both celiac disease and ADHD, there are reports of many disorders involving morphological and functional changes to the central and peripheral nervous systems. In celiac disease, dietary intervention has been demonstrated to result in improvement or resolution, in most cases of these symptoms. In a few anecdotal reports (see appendices one and five, Colquhoun & Bunday, 1981 ), similarly positive results have been accomplished through dietary exclusion of gluten or gluten and dairy in ADHD. When two groups of pathogens, as with gluten and dairy, can be demonstrated as the cause of attentional problems and abnormalities in CNS morphology and perfusion in celiac disease, the assertion of similar possibilities in the context of ADHD does not seem unreasonable.
Reduced essential fatty acid (EFA) levels have long been recognized as over- represented among ADHD patients (Aman, Mitchell, Turbott, 1987; Colquhoun & Bunday 1981; Mitchell, et al. 1987; Stevens, Zentall, Deck, Abate, Watkins, Lipp, 1995; Wainwright 1992 ). According to Colquhoun and Bunday (1981), "A 1932 description of behaviour in children with coeliac disease who have a fat malabsorption problem could be one of the earlier descriptions of hyperactivity". There is thus cause to suspect that many of the soft neurological signs associated with ADHD (Martin, Welsh, McKay, Bareuther, 1984) may be associated with EFA deficiency (Mitchell et al. 1987), as has been suggested to apply to celiac patients with neuropathic symptoms (Cooke & Holmes, 1984). It is these neurological signs which led to the early characterizations of ADHD as "minimal brain damage" (Mitchell et al., 1987) although it was many decades before definitive evidence of altered morphology of the brain, other than reports on pathological electrical activity, would emerge in connection with what is now called ADHD. With the use of contemporary diagnostic technology, we are now aware that only about 5% of ADHD children show solid evidence of brain damage (Mitchell et al. 1987). There are developmental and morphological abnormalities, but the term 'damage' seems to imply mechanical damage, which does not appear to apply to a large majority of ADHD subjects.
Moreover, in spite of the EFA deficiencies noted earlier, several controlled studies indicate that EFA supplementation has only minimal, if any, remedial value in the treatment of ADHD patients (Aman et al. 1987; Wainwright 1992). The explanation for this situation remains unclear (Mitchell et al. 1987; Stevens et al. 1995), but speculation of malabsorption, or reduced ability to convert fatty acids to longer chain unsaturated fatty acids, and increased metabolism of , or impaired systemic or cellular transport of EFAs, have all been included in some of these discouraging reports (Mitchell et al. 1987; Stevens et al. 1995; Aman et al. 1987; Colquhoun & Bunday 1981; Homan, Johnson, Hatch, 1982; Stevens Zentall, Abate Kuczec, Burgess, 1996; Wainwright 1992; Ziesel 1986). The possibility of microvillous damage, perhaps resulting from dietary/autoimmune dynamics, seems to have been given little, if any, attention. The microvilli are the site of absorption of fats, for lymphatic transportation to the liver. As fats are not water soluble, they can not be absorbed directly into the circulation (Hoggan 1997c). The unique nature of fat absorption, in combination with common EFA deficiencies among people with ADHD, provides what may be an important window through which to view this condition.
A revealing note in all of this is that the established connection between EFA deficiency and ADHD (Mitchell et al. 1987; Stevens et al. 1995; Aman et al. 1987; Colquhoun & Bunday 1981; Homan, Johnson, Hatch, 1982; Stevens Zentall, Abate Kuczec, Burgess, 1996; Wainwright 1992; Ziesel 1986) may suggest an answer to one previously unexplained anomaly in ADHD. The high male to female ratio in ADHD has been suggested to be a function of gender differences in EFA requirements (Colquhoun & Bunday 1981). As one group put it: "Male animals require approximately three times as much EFAs as females for normal development" (Mitchell et al. 1987).
An additional factor related to essential fatty acids is that exorphins (opioid peptides) from milk and wheat can block PGE formation from dihomogamma-linolenic acid (DGLA) (Mitchell et al., 1987). PGE is a series 1 prostaglandin involved in a variety of immune and circulatory functions (Erasmus, 1996). This may provide another clue to the etiology of some of the reported increases in immune system anomalies (Warren, Odell, Warren, Burger, Maciulis, Torres, 1995; Mitchell, et al, 1987; Stevens et al. 1995) and abnormalities in neurotransmission in many cases of ADHD (Hoshino, Ohno, Yamamoto, Kaneko, Kumashiro, 1985; Greensberg, Coleman, 1976; Halperin, Newcorn, Kopstein, McKay, Schwartz, Siever, Sharma, 1997; Coleman, 1971 ) and celiac disease (Chiravalloti, et al. 1997; Hallert, et al. 1982).
EFAs have a significant impact on phospholipids in the brain. Ziesel (1986) tells us that: "Essential fatty acids needed by the brain are obtained from the diet They traverse the blood-brain barrier by translocation through endothelial cell membranes. Phospholipids are synthesized within the brain from these fatty acids and glycerol. Fatty acids are also precursors for the synthesis of prostaglandins, which are important neuromodulators". Thus, EFA deficiencies, as found in ADHD, are likely to impact upon brain structure, neurotransmission, as well as immune system function. Such deficiencies of essential fatty acids are also widely recognized as a common feature of celiac disease.
Others have shown that long chain, omega 3 fatty acids are very concentrated in nerve tissues, and some omega 6 fatty acids are present in large quantity as functional and structural components in cerebral gray matter, and the retina (Wilens, Prince, Frances, 1995). The ingestion and metabolism of these fats is critical to brain and nerve function, hence the term 'essential'. The variety of neuropathic symptoms often reported in ADHD may find at least some explanation in the EFA deficiencies which are now known to be common in ADHD.
Differentiation between ADHD subjects with omega 6 deficiency and those with omega 3 EFA deficiency may also provide a greater understanding of etiological factors in the identified sub-categories of ADHD. While omga 3 deficiencies predominate among those presenting with hyperactivity (Mitchell et al. 1987), behaviour problems, temper tantrums, sleep, learning, and health problems, are parallelled by findings in animal studies (Stevens et al., 1996) further re-reinforcing the suggestion of a relationship. Additionally, animal studies imply that the increased thirst often found in ADHD subjects may also be attributable to deficiencies in omega 3 fatty acids (Wainwright, 1992). It is of interest to note that the effects of DHA deficiency, a derivative of omega 3 fatty acids which may also be found in fish, marine animals, and some organs, require long term deficiency before the composition of the brain is altered (Wainwright, 1992). If the postulated connection exists, it is chronic, and is thus unlikely to be remedied by interventions of short duration, as are often employed in dietary investigations, if it can be remedied at all. Conversely, "A high rate of speech difficulties was found among the children with low arachidonic acid levels" (Mitchell et al.,1987). These latter are synthesized from the omega 6 EFA, linoleic acid, and they are found in meat, eggs, and milk (Erasmus 1996). Perhaps the case of aphasia in celiac disease, mentioned earlier (Scully, et al., 1988) which slowly resolved after several months of excluding gluten from the diet, reflects a deficiency in omega 6. The description is very consistent with the explanation provided by Mitchell et al. (1987) If so, perhaps the cause of language learning problems in some cases of ADHD is associated with a similar problem with absorption of EFAs.
There is also evidence that "....cognitive and linguistic problems appear to precede hyperactivity" (Sandberg 1996). Perhaps, with a greater understanding of EFA deficiencies, the specific presentations of individual ADHD patients' EFA levels may provide a means of differentiating sub-groups, ultimately revealing a food intolerance disease, or losses in absorptive capacity.
An interesting contradiction comes to us from Aman et al. (1987) who report: "The subgroup analyses... failed to indicate a differential response for individuals who were initially low or high on these substances," thus undermining the therapeutic use of EFAs in ADHD. But this result may be interpreted in another manner. If malabsorption is occurring in varying degrees, due primarily to variations in microvillous morphology, or reduced bile delivery to the duodenum, or both, then a more EFA deficient child would be less likely to benefit from supplementation. This would be true because the more deficient individual would likely be experiencing a more pervasive malabsorption pathology, rather than a dietary insufficiency of EFAs. On the surface then, it is probably quite correct to say that EFA supplementation is not an effective therapeutic answer, but this does not obviate EFA deficiency as a very important factor in ADHD signs and symptoms, and it does reinforce the notion of a pathological connection. Colquhoun and Bunday(1981) state: "Since an EFA deficiency itself leads to a defect in fat absorption which will exaggerate the deficiency, a vicious circle could result".
There is also the possibility of reduced cholecystokinin (CCK) production in the duodenum (Tortora & Anagnostakos, 1989, p.751), due to damage caused by food intolerance (Domschke, Bloom, Adrian, Lux, Bryant, Domschke, 1989). Absence of this hormonal messenger, which signals the gall bladder to contract in response to fat consumption, could also lead to both a deficiency in EFAs, as well as a failure to respond to supplementation (Minich, Vonk, Verkade, 1997).
Malabsorption due to slight damage to the mucosa of the small intestine would be very likely to have a large impact upon fat absorption, since fats are absorbed at the microvilli, into the lymph system, rather than through the intestinal wall into the circulation, as with other nutrients (Hoggan, 1997c). The microvilli extend, with the exception of brush border enzymes, furthest into the intestinal lumen, and may sustain damage more quickly than the underlying structures.
Deficiencies in dietary intake of EFAs appear to have been ruled out in most of these reports connecting EFA deficiency and ADHD, and we are left to explore other explanations for this deficiency. In our exploration, we may find evidence to suggest some features of malabsorption diseases associated with food-protein intolerance. In fact, there is considerable evidence connecting gluten and dairy consumption with ADHD.
Interestingly, refined sugar may also influence central serotonin levels. It is a substance which has long been suspected to be an initiator of hyperactivity symptoms. This has been repeatedly refuted in controlled studies. Although more refined sugar consumption has been reported among ADHD subjects, it appears to reduce activity levels among both normal controls and experimental subjects (Rapoport, 1986) and it has been demonstrated to reduce performance on school achievement tests (Egger, Stolla, McEwen, 1992). Perhaps sugar is at work in attentional deficits, rather than in hyperactivity. The hyperactivity might follow, as something akin to a rebound reaction.
It seems that "dietary alterations in precursor availability can modify neuronal activity" (Young, 1986). The availability of tryptophan through increased insulin production, in response to sugar ingestion, increases uptake of competing large neutral amino acids into muscle cells. This increases the relative serum concentration of tryptophan, which is resistant to insulin. The relative increase in serum tryptophan, following a rise in insulin, leads to a competitive advantage to tryptophan, for transport across the BBB. Increased tryptophan has been asserted to lead to increased levels of serotonin in the brain (Krassner, 1986; Fernstrom 1986; Wurtman, 1986; Ziesel, 1986). Increased tryptophan can also lead to drowsiness, and induction of endorphin analgesia (Ziesel, 1986). Poor attentional performance would seem consistent with this scenario. Although a bit of a digression, the importance of which will become apparent shortly, it has also been shown that "oral or intravenous administration of gluten exorphins A5 and B5 can influence the regulation of postprandial insulin release"(Fukudome, Shimatsu, Suganuma Yoshikawa, 1995; Scott, Cloutier, Kleemann, Woerz-Pagenstert, Rowsell, Modler, Kolb, 1997; Scott, 1996).
Thus, consumption of sugar or gluten should, other conditions being equal, predict reduced activity levels. It is of interest to note that hyperactive children appear more likely to consume greater quantities of sugar, while the same group also appears to have a superior appreciation of the stimulant effects of caffeine (Rapoport, 1986) which offers some interesting vantage points for considering some of the symptomology of ADHD.
There is also familial evidence to suggest that serotonin deficiency may be involved in aggressive behaviour, and a poor long-term prognosis for that behaviour (Young, 1986; Halperin, Newcorn, Kopstein, McKay, Schwarn, Siever, Sharma, 1997). There appears to be something of a contradiction here. Hypoarousal is not easily associated with aggressive behaviour. To add to the confusion, sugar has recently been demonstrated to alter EEG patterns among subjects with food-induced ADHD (Uhlig, Hoshino, Hashimoto, Okano, Kumashiro, 1993). These are the contradictory findings reported in the literature. If the in- vivo action of exorphins is factored into this array of conflicting reports, perhaps some of that contradictory complexity will be reduced.
As was mentioned earlier, dietary precursor availability can affect neuronal activity (Krassner, 1986). Variations can occur in neurotransmitter release, as a function of variations in diet " thereby allowing one's nutritional state to affect one's behaviour"(Wurtman, 1986) and specific neuronal cells can synthesize neurotransmitters if the precursor is available in the diet" (Lovenberg, 1986). Tyrosine is the amino acid precursor of dopamine and epinephrine. "Brain tyrosine levels are most conveniently increased by ingesting pure tyrosine alone or with a carbohydrate (to lower plasma levels of competing LNAA)" (Lovenberg, 1986). Meals high in protein and carbohydrates also tend to raise tyrosine levels in the brain (Ziesel, 1986). Thus, the reported inverse relationship between urinary epinephrine levels and both fidgeting and aggression among normal children (Hanna et al., 1996) offers some interesting insight when we look at reports that ADHD subjects show significantly lower urinary levels of epinephrine than in controls (Hanna et al., 1996). Abnormalities in iron absorption may suggest an explanation for this dynamic.
Sandstead (1986) has suggested, on the basis of animal findings, that iron may be required for dopamine receptor function in the caudate nucleus. Monoamine neurotransmitters, principally dopamine, appear to affect neuronal communication in regions of the brain involved in executive functions (Castellanos, 1997) which, by definition, is a problem for ADHD patients (DSM IV). Given the issues surrounding problematic uptake in iron supplementation associated with ADHD (Olki, honig, Helu, Howanitz, 1983; Lozoff, Viteri, Urrutia, 1982), in conjunction with evidence of iron requirement for receptor function (Sandstead, 1986), this may be a very important interface of two dietary issues in ADHD and celiac disease, as will be discussed shortly.
Kapusta et al. (1989) have identified exogenous and endogenous peptides as regulators of kidney function. Urinary dysfunction is reported as very common in ADHD (Maizels, Gandhi, Keating, Rosenbaum, 1993). The data on monoamines provide quite convincing evidence for the belief that there may be an interplay between diet and behaviour which is mediated by alterations in neurotransmission. This can be important at all levels of under-nutrition (Zeisel, 1986 ). Malabsorption is one means by which under-nutrition may occur in a clinically obscure fashion ( Hoggan, 1997a; 1997b).
Since the parathyroid gland is involved in regulation of calcium and magnesium metabolism, there is another connection with food intolerance provided by the report that IgA class endomysium antibodies, which are a very specific indicator of celiac disease, can cross-react with parathyroid tissue (Kumar, Valeski, Wortsman, 1996), and low magnesium levels have also been associated with functional hypoparathyroid (Bertelloni, 1992). Recent investigations reveal that the incidence of magnesium deficiency was found in 95% of ADHD patients studied, and that remediating that deficiency can result in significant improvements in ADHD symptoms (Starobrat-Hermelin, Kozielec, 1997; Kozielec, Starobrat-Hermelin, 1997). Similarly, all adult-diagnosed celiac patients demonstrate some level of bone demineralization, compared to the general population, regardless of dietary compliance (Green, 1997). Many celiac subjects who demonstrate diminished calcium levels show improvements to serum calcium after magnesium supplementation alone (Cooke & Holmes, 1984), and magnesium supplementation has been shown to aid bone remineralization, to a greater degree than calcium and vitamin D supplementation, among treated celiacs (Cooke & Holmes,1984). One report asserts that all of a group of celiac patients who underwent magnesium supplementation demonstrated significant bone remineralization (Rude & Olerich 1996).
Some dietary deficiencies of trace minerals may also affect neurotransmitter function (Lovenberg, 1986). For instance, iodine deficiency can have a devastating impact on brain maturation and function (Sandstead, 1986).
The rationale presented for oral iron supplementation is: "Oral iron was used because it is the treatment of choice, with a therapeutic response parallel to that of intramuscular iron, and because of the slight risk associated with parenteral administration of iron" (Lozoff, Viteri, Urrutia, 1982). In spite of the rhetoric, oral iron did not help. We are left to wonder why. Lozoff et al. (1982) suggest the possibility of malabsorption, but found no other evidence to support such a possibility and therefore dismissed it. Many cases of celiac disease are identified through investigation of the singular presentation of iron deficiency anemia which is resistant to oral supplementation (Volpe, Festini, Torre, Lucchesi, 1997; Barton, 1997). We must wonder why malabsorption would be dismissed in ADHD with associated iron deficiency that is resistant to oral supplementation (Lozoff et al., 1982). Celiac disease can cause selective malabsorption of iron (Volpe et al., 1997). The asserted association, in some cases of iron deficiency, of deficiency of vitamin B12 and folic acid (Bushnell, 1992) should also increase suspicion of malabsorption, but iron deficiency alone should significantly elevate suspicion of malabsorption disease (Carroccio, Iannitto, Cavataio, Montalto, Tumminello, Campagna, Lipari, Notarbartolo, Iacono, 1998).
Another problem can lurk in our desire to provide children with a healthy diet We may err in what we feed them: " too much fibre in the diet will render available iron unabsorbable" (Bushnell, 1992). This is arguably the result of phytic acid entering into combination with the iron, thus forming a bond which cannot be broken by the enzymes in the gut (Lindeberg, 1997). In support of this suggestion, iron deficiency is also reported as overly common where "cereals and legumes are the primary source of energy and protein" (Sandstead, 1986).
Further to the relationship between iron deficiency and ADHD, Cantwell is reported to have " detected 'soft' neurological signs as long as six months after treatment for iron deficiency anaemia at 6 to 18 months"(Lozoff, et al., 1982). Also, learning disabilities and attention deficits are sometimes attributable to iron deficiency anaemia (Bushnell, 1992).
Zinc deficiency has also been reported in ADHD. Zinc deficiency indirectly inhibits some normal essential fatty acid processes through inhibition of specific enzymatic activity (Mitchell, et al., 1987; Colquhoun & Bunday, 1981). Zinc deficiency, as with iron deficiency, can also result from elevated levels of fibre with phytic acid in the diet, as with cereals and legumes (Sandstead, 1986). Animal studies in zinc deficiency have revealed developmental delays as well as alterations in neurotransmitter concentrations (Sandstead, 1986). Zinc deficiency may also be involved in inhibition of growth and is also reported in celiac disease (Cooke & Holmes, 1984).
In total then, mineral deficiencies, individually, or in combination, may result in some ADHD symptoms, and many of these are suggestive of dietary deficiency, or metabolic abnormalities. Patients with celiac disease appear to suffer similar deficiencies in most or all cases.
Perhaps the earliest work which showed improvement in ADHD subjects' EEG patterns, in response to diet, was conducted by Kittler et al.(1970 ). While they recognize that EEG patterns have long been known to be abnormal in some allergic children, they also believe that improvements of such EEG abnormalities had not previously been connected to dietary changes in those with learning problems.
The EEG abnormalities in food-induced autoimmunity such as celiac disease also has a surprisingly long history in Europe, although I can find no reports of such work published in English. In a translation from German, Paul et al. (1985) tell us that Sidor & Mitarb and Karczewska & Mitarb suspect this mechanism to be the direct effect of the gluten upon the central nervous system and hence on the brain wave curves, while Paul et al. have reported their own investigations using EEG, in addition to other techniques. Their EEG investigations revealed that 38 of 58 (66%) of the celiac children studied showed pathological EEG changes which increased with increased duration of gluten consumption, and that the long-term compliance with a gluten-free diet decreased the probability of pathological readings. They go on to provide evidence for a correlation between the extent of mucosal damage, and the duration of pathological EEG patterns and contend that the psychological signs in celiac children reflect a direct or indirect influence of gluten ingestion, and that damage to the intestinal mucosa is always accompanied by pathological brain waves in the celiac children studied. Several interpretations for this are: 1. People with damaged small intestines absorb more toxic substance, resulting in the pathological changes, or; 2. Toxic, gluten-derived proteins and peptides may cause the pathological changes; 3. Both of the above dynamics contribute to the pathological changes.
Kozlowska (1991) has reported a very similar incidence of EEG abnormalities in 71% of the celiac children studied. She has identified these abnormalities as the same as those found in ADHD.
The importance of the startling report from Uhlig et al. (1997) is difficult to over-emphasize. It provides objective evidence for a connection between food intolerance and ADHD. This group has reported their recent finding that topographic mapping patterns can be manipulated by changes to the diet among ADHD subjects. Refined sugar, milk, and gluten proteins were most frequently implicated in the ADHD-specific abnormalities identified in topographic EEG mapping.
Of course, there is always the semantic difficulty that if similarly pathological EEG patterns are present in two conditions, then the patterns are sometimes discredited as characteristic of one condition. For instance, one report indicates that some EEG patterns under specific conditions may be characteristic of ADHD, but under other circumstances could include some other categories of mental illness (Levy, Ward, 1995). The converse argument, that there is overlap between these conditions, also seems supported by the same evidence. But perhaps the work of Ulig et al. (1997) in demonstrating EEG changes associated with dietary factors among ADHD subjects will finally facilitate an end to such debates.
Published replications of this group's findings may finally induce pediatricians, teachers, and parents to engage in a careful search for dietary pathogens prior to leaping for easy pharmacological answers. Schmidt et al. (1997) claim that a "biochemical rationale for the allergy hypothesis is still lacking". This may not be accurate. If we harken to Paul et al.(1985) again, they have asserted that in celiac children, the pathological brain wave patterns are the direct or indirect result of gluten ingestion, and that damage to the intestinal mucosa is a necessary precondition to the EEG abnormalities they studied. But this damage might not need to include villous atrophy among non-celiacs who are suffering from similar symptoms. If we are looking for a condition in which either dietary antigens or toxic substances can enter the blood, then a condition of permeable intestine may suffice. Animal and human studies demonstrate that a variety of forms of gluten-induced damage can occur in the absence of celiac disease (Hadjivassiliou, Gibson, Davis-Jones, Lobo, Stephenson, Milford-Ward, 1996; Thibault, Coulon, Roberge, 1988; Levine, Briggs, Harding, Nolte, 1966; Hudson, Purdham, Cornell, Rolles, 1976; Doherty, Barry, 1981 ). This principle may also apply to a variety of mental illnesses.
As mentioned earlier, Husby et al.(1985) have demonstrated that many apparently healthy adults are allowing the passage of gliadin proteins into the blood. Antigliadin antibodies found in the sera of 15% of a random sample in Iceland (Arnasson, et al, 1992), and 4.75% of healthy blood donors in the USA (Not, et al. 1996) suggest that many of us absorb partly digested proteins into our blood. Fukudome and Yoshikawa have characterized 5 distinct opioid-acting sequences of amino acids in the pepsin digests of wheat gluten, which are repeated, sometimes as many as 15 times in a single gliadin molecule (Fukudome, Yoshikawa, 1993), dubbed 'exorphins' (Zioudrou, et al., 1979). Others have also isolated such peptides in casein, one of the proteins in milk (Mycroft, Wei, Bernardin, Kasarda, 1982).
Perhaps originating with Dohan et al. (1966), and being continued by Reichelt et al. (1997) the investigation of dietary proteins in gluten-containing cereals and milk, as regards a variety of mental illnesses, has led toward a perspective that an interaction between the opioid peptides in these foods, and a genetic predisposition, may combine to result in a variety of manifestations. Clinical trials have shown that some schizophrenics benefit from the dietary exclusion of gluten and dairy (Dohan, et al.,1969; Singh & Kay, 1976; Reichelt, Sagedal, Landmark, Sangvic, Eggen, Helge, 1990a; Reichelt, Ekrem, Scott, 1990b ). Other work shows that many autists benefit from the same diet (Reichelt, Knivsberg, Lind, Nodland, 1991).
Lovenberg (1986) has indicated that diet could influence behaviour through " the presence of psychoactive substances in food. Such compounds may bypass neurotransmitter synthesis to directly activate or inhibit specific cell types in the brain". And this is the perspective herein postulated to be at work in many cases of ADHD. The exorphins are thought to either be transported to the brain, and function in a manner similar to opiates (Zioudrou, et al., 1979) resulting in reduced alertness of some parts of the brain, or to inhibit the breakdown of other peptides, thus resulting in elevated levels of endogenous opioid peptides within the brain (Hole, Lingjearde, Morkrid, Boler, Diderichsen, Saelid, Ruddd, Reichelt, 1988).
In support of this hypothesis, it has been demonstrated that "children diagnosed as having ADD of some severity excrete peptide-containing complexes in the urine" (Hole, et al., 1988). As was previously discussed, there is considerable overlap between these groups, and there also seems to be some relationship between the patterns of urinary complexes and the presence or absence of hyperactivity (Hole, et al. 1988). Although the exorphin hypothesis does not require breach of the BBB, it may be possible that the cytotoxicity of gliadin peptides (Atkins, 1986) provides such a breach.
Testing for anti-gliadin antibodies has rendered a range of positive results. The lowest incidence reported in a random population is 2.3% (Catassi, Ratsch, Fabiani, Rossini, Bordicchia, Candela, Coppa, Giorgi, 1994), while the highest reported incidence is 15% (Arnason, et al., 1992). When coupled with the reported incidence range of ADHD, there is an interesting, although not completely congruent picture, as the most common figures suggest ADHD in 2% to 10% of school aged children (Rowe, 1988, Boris & Mandel, Castellanos, 1997). The comparison becomes striking when we revisit the proportion of celiac children who demonstrate ADHD-appearing, EEG patterns (Paul et al., (1985); Kozlowska, (1991) which suggest that about two-thirds of celiac children exhibit such abnormalities. If we can assume that the 70% proportional incidence of ADHD symptoms found in celiac disease could also occur in a population demonstrating anti-gliadin antibodies, then the reported incidence of such antibodies in random populations, 2.3% to 15% would suggest an incidence of ADHD at 2% to 11%, which is surprisingly close to what has been reported. It is such points of convergence that form the central thrust of this thesis. Of itself, one such point may not be interesting. Several such points of convergence must begin to pique our interest, and a significant number of such points may demand consideration. Table 1 offers an outline of twenty significant points of convergence which may be found between ADHD and food intolerance disease. It also offers seven significant points of convergence between elevated anti-gliadin antibodies and ADHD.
The process involved in the exorphin hypothesis, as it relates to ADHD is shown on the following pages. There are some cases, perhaps many, of ADHD that probably do not derive from these dietary factors. Many such cases would likely fall outside the genetic coding for the HLA factors most suspect in the case of food intolerance disease and thus, food-induced ADHD.
Only further research will plot the precise boundaries of food-induced ADHD. That some cases of ADHD are caused or exacerbated by dietary factors is undisputed. Some may believe that those numbers are very small, as is suggested by the research conducted within a pharmacological paradigm. Work cited earlier, which has moved to the periphery of that paradigm, has demonstrated an increased incidence of food-induced/exacerbated ADHD to a slight majority of the subjects studied.
Other than examinations of urinary peptide excretion in ADHD, there has been little work directly investigating exorphins. As one may unwittingly substitute one source of exorphins for another, trials involving single substance and single food-group exclusion, are unlikely to identify at least some of the cases of ADHD resulting from exorphins. In the interim, as we await more research which directly investigates the exorphin hypothesis, it seems useful to offer the following outline of the postulated process of the action of exorphins in ADHD:
Figure 4.1 HLA-B8 Distribution in Europe [need figure]
This is the first element of the model. While the HLA-B8 group does not include all of those who have celiac disease, it is a genetic marker which is highly associated with gluten intolerance. As such, the European distribution of this genetically determined element of the immune system indicates that members of this group are either reduced in the gene pool, in direct proportion to the period of exposure to cereal grains. While the focus of this document would suggest that childhood disease and pre-reproduction deaths would account for some of this distribution of HLA B8, population displacement is also a probable contributor.
It may therefore be postulated that the morphine-like properties of exorphins, or inappropriately conserved endogenous opioids, impact upon behaviour. When binding occurs within the brain, many problems may arise, as has been suggested in discussions of points of convergence between food intolerance and ADHD. As vasoactive peptides, they may play a role in reduced blood supply to parts of the brain. They may anaesthetize parts of the cortex involved in speech production and/or language learning and/or mathematical learning. And they may interfere with some executive functions through reducing activation and perfusion of those parts of the brain.
Our limited grasp of neurotransmitters makes it difficult to imagine exactly how changes from attachment of endorphins and other endogenous peptides, to competition with these latter, and attachment of exorphins may explain the behavioural and attitudinal changes witnessed in ADHD, yet we do recognize such changes, and accept them as normal, when children and adults are diagnosed with food intolerances. We also recognize such changes in those who are addicted to opiates.
Envisioning the model in such a simplistic, three stage form may suggest a superficiality which is inappropriate. The process outlined is a highly complex one, and the finite representation herein may incorporate some errors, and lead to misunderstanding. This should impugn the author, not the hypothesis.
The web on the following page offers yet another visual perspective which may better represent the complexity of the postulation embodied here. It is an attempt to depict some of the interconnections between the signs and symptoms of ADHD and celiac disease. Figure 4.2 is thus offered as an imperfect representation of these associations of symptoms and signs of celiac disease and ADHD.
There is some suggestion of a detoxification dynamic at work in some successful dietary interventions in ADHD. "In several children the initial improvement produced by the diet was preceded by a deterioration in behaviour" (Egger, Carger, Graham, Gumley, Soothill, 1985). Such initial deterioration might represent withdrawal from dietary exorphins, and it is important to anticipate such a response. Withdrawal from an addictive substance with analgesic function might erroneously be characterized as a negative response to a short-term dietary intervention and should suggest patience, rather than a rush to judgement and abandonment of the diet Some of the delay in responding to re-introduction of a suspect food is the result of healing and reconstruction of the intestinal mucosa. The long period of gluten challenge, of up to two years, required in some cases of celiac disease (Chartrand, Seidman, 1996) may well be the result of a healed mucosa functioning in a protective fashion, preventing harmful proteins, peptides, and toxins from entering the blood. The expectation of a rapid response to dietary intervention, although it sometimes happens in ADHD and celiac disease, is misplaced. There is also the learning phase, in such interventions, which many food intolerance patients can attest to. In the early stages of compliance with such a diet there are many painful "learning experiences" resulting from mistakes.
Trials of fad diets, however, may not be the answer. All too often, compliance is difficult, and may wane over time, if there are only subjective, arguable results reported. This problem can be addressed by several means. Assuming that thyroiditis and hypoglycemia have been ruled out, serum testing for gliadin antibodies is an inexpensive, non-invasive test. For less than the cost of a month's supply of stimulant medication, such testing would clearly identify intestinal permeability, suggesting both the need for dietary intervention, and the specific nature of one of the appropriate exclusions.
Serum antibody testing for celiac disease, in the form of IgA anti-endomysium as well as IgG and IgA antigliadin antibodies ( see appendices four and six, regarding serological testing), in combination with testing for IgA deficiency, although more expensive than the first option suggested, offers a valuable tool both for excluding celiac disease, and for identifying intestinal permeability in ADHD. The range of possible interventions is broadened by this more extensive testing.
The presence of IgA antibodies are more suggestive of celiac disease and hence, an increased risk of malignancy, pulmonary abnormalities, and associated autoimmune diseases which should lead to further testing to definitely rule it out. The presence of IgG antibodies, if there is no IgA deficiency, suggest a permeable intestine. As has previously been discussed, such intestinal permeability may point to the possibility of a dietary resolution to ADHD symptoms.
As teachers, we need to protect the children in our charge, not aid in a process that silences their cries for help. Whether those cries are in the form of misbehaviour in our classes, or an apparent inability to focus their attention on the task at hand, they are speaking to us in the only language they have, about an illness which they do not understand. It is up to us to come to understand it.
Teacher preparation programs should include discussion and opportunities for contemplation of some of the ethical issues associated with teacher participation in evaluations of students toward ADHD diagnoses. These programs should also provide instruction related to the diagnostic and treatment processes currently employed with cases of suspected ADHD. Entering employment as knowledgeable teachers, they will thus have a choice about whether to participate in the process in a knowledgeable manner, or to exclude themselves on the basis of their own ethical determinations on the topic.
As knowledgeable participants in the process, they will be in a position to ask if testing for thyroiditis and hypoglycemia has been conducted. Such prior testing could even be made a condition of their participation in the process, should the teacher feel strongly enough about this issue. Teachers might also ask the student and parents to consider antibody testing, prior to initiating an evaluation process which is aimed at possible stimulant or other chemical therapies.
Those volunteers with Reye's syndrome, a history of a hypoxic anoxic event, heavy metal toxicity, significant head trauma, or central nervous system infection, as outlined by Barkley (1990) would be excluded. While Barkley includes cerebral-vascular disease as a condition which should be included in the differential diagnosis of ADHD, such disease has repeatedly been reported in the context of occult celiac disease, and would therefore not be an appropriate element of the differential diagnosis for the purpose of the proposed investigation.
Current use of stimulant or other medications would be noted, and any dietary or other treatments currently employed would require investigation, and possible exclusion of the subject, where appropriate. Current practices of dietary supplementation such as the use of multivitamins would also require attention, especially regarding the nature of binders used. It might also be useful to standardize supplements for all participants during the course of the study. A uniform starting date for the trial would be useful, especially if it could be coordinated with school reporting periods, and end prior to, or begin after occasions where there is greater temptation to "break" the diet, such as during the Christmas holiday.
Extensive instruction, regarding the diet and its many pitfalls, would be necessary, and should be conducted by the teacher and a qualified dietician.
Baseline tests:
Such an investigation would likely be attractive, primarily, to parents and children where the symptoms were quite severe. Those whose personal perspectives opposed the use of stimulant medications would also be likely to be over-represented among these volunteers. Those best suited to meet the economic, social, and time-use challenges of a gluten-free, dairy -free diet would also be likely to be over-represented in this group. Such an initial foray into this research would probably not be inviting to a representative sample of ADHD subjects, and the results, regardless of how positive, could only be taken as a herald for further research in this area. Still, such a clinical trial could offer great insight into the murky world of ADHD.
Following Naloxone screening, and antibody testing, clinical trials of gluten-free/dairy-free interventions in ADHD would offer support for the use of serological testing of ADHD children as an objective diagnostic tool and as an indicator of appropriate therapeutic intervention.
Young offenders who are incarcerated might well benefit from such dietary restrictions, and their periods of incarceration might provide a very important service to society and to these youngsters.
Epidemiological work, perhaps in the form of anitbody testing in large groups of ADHD children, would also be revealing. Perhaps this is the tool that may identify many of those ADHD patients who will benefit from dietary interventions.
Further refinement of urinary peptide filtration and characterization may also provide a diagnostic tool for some sub-types of ADHD, as well as providing a clear indication of who may benefit from dietary interventions. Investigations of the application of the exorphin hypothesis to ADHD might also be conducted in a variety of manners and methods which the author has not considered.
A further limitation lies in the difficulty in implementing such dietary interventions. Gluten and dairy proteins pervade the food supply in industrialized nations, and often do so in occult forms. It is also a challenge to investigate or implement such dietary interventions in the context of an under-informed medical community.
Nutritional issues are given little or no attention in most of our medical training programs, and dietary issues are often dismissed as a result of such deprecation by some adherents to conventional medical wisdom. Despite these limitations, the impressive body of evidence which suggests and supports this perspective imparts an urgency to the call for further research in this venue.
We are not just discussing 2% to 10% of the school children who have difficulty settling to their work, or focussing their attention. We are talking about a large segment of the population, perhaps as much as 30%, which is increasingly inundated with gluten and dairy proteins in almost all or our processed food. Their immune systems are compromised. They are more likely to suffer from malignancy, autoimmunity, neuroses, or psychoses, or perhaps all of these.
Teachers can participate in fostering social wellness, or continue to aid in the process that masks symptoms of treatable ailments so the illnesses will continue to go untreated and, in some cases, result in deadly and debilitating sequelae.
Dear Ron,
A moment's peace ! Lewen is at school! Thank you for your letter, I will endeavour to give you as much info as you want. You may do with it whatever you want; there is so much to remember. Perhaps expressing some of these last five years with Lewen will be a relief of sorts - I know you will understand the deep meaning of that.
We have all been emotionally and physically drained as well as socially deprived . Funny really, all I had to do was skip the bread isle of the supermarket! But no bread and jam or toast or cake with my tea is just not cricket - I mean I'm English for Christ's sake! Change is always confronting but the benefits speak for themselves. Thank you once again for your interest in Lewen.
PRE-LEWEN: Two children, Sarah 10, Nicholas 9. Civilized, balanced, socially active. OK. So we sat around our table and discussed having another addition to the family...everyone in favor, we'd share everything...waited. nine months passes...a very anxious expectant family.
LEWEN: Born 18/12/91, three weeks late, dry birth due to ruptured membrane four days earlier. Consequence - Lewen is born with HIB meningitis. Life-threatening situation, antibiotics, oxygen, humidicrib. First feed eight hours later is disastrous as is every other feed for next nine months. Child would suckle one mouthful, arch his little back into a ball, then pull away; then try to suckle again; hated feeding generally. It looked like feeding was somehow very painful for him. Help from chemists, doctors, specialists, clinics, etc. led us to try everything on the market At six weeks, paediatrician's synopsis, "most extraordinary!", can offer no advice. Constantly on the move, loud, a restless sleeper waking every couple of hours till age three and burning rubber the moment his feet touch the floor.
At eleven months an evening meal abandoned as we rush screaming child to hospital, suspecting food poisoning; turns out to be a stool which had blistered his bottom in a cup-sized ring, quickly relieved with paw paw ointment. Walking by nine months, he managed to climb to top shelf and drink bleach at age one. Trees around house cut down to keep him off the roof, (two storey at front), safety harness attached to 20 metre lead, a bell attached to his clothes, neighbours on the lookout, Lewen's first first year of life was intense, ours desperate.
On the positive side, Lewie has a fantastic memory; even though he doesn't seem to dwell on anything and it is surprising the detail he can communicate when it suits him. He is very dexterous and loves building things. Kathe, our good neighbour, said he seemed to be driven, as though trying to take his mind off whatever is upsetting him. He was like a butterfly on speed! More in-depth medical merry-go-round and allergy testing with no more help. He was totally over the top, could not still or concentrate for more than a minute on anything, showed little affection even though there were four of us craving it; we were beginning to suspect autism. One paediatrician's advice at eighteen months, "This is a behavioural problem, perhaps we should consider foster care!"
New GP in town (20 others), who listens, observes, understands. Places Lewen on Serfontain Clinic waiting list for assessment. At age two, Lewen is diagnosed as chronically hyperactive (ADHD). Gov't. regulations are four years minimum before he can be given medication for the condition! With a stack of documentation supporting Lewen's condition, we appeal to the Health Dept. and wait. He began medication (dexamphetamine) at three years of age. Yesssssssssssss!
LEWEN MEDICATED: What an immediate change! He could actually watch a five minute TV program and turned the pages of a book as though re-discovering them instead of speed reading. A much happier kid, more affectionate, and although there was an initial weight loss, he regained it and actually put on weight. He was still a tornado but at least his concentration improved immensely. It was great but no panacea.
Christmas 1995 we miss script renewal by four days, we spend five days over Christmas with Lewen unmedicated. Disaster! Day five, mother hospitalised for ten days with nervous exhaustion. Camping holiday postponed, teenagers devastated, Lewen rampant.
Now seeks adult supervision, clingy when dropped off at school. This year he started kindergarten and we decided not to say anything to the school about his condition and instead medicated him prior to him going; we weren't sure if we had a bored genius or struggling child! If there was a problem, they would let us know. (Medication was given at 6am, 8:55am, 3 pm.) It is now May and Lewie is doing well at school and loving it. Wants to learn, becoming more social, the class clown and popular.
GLUTEN-FREE: Kathe once more to the rescue with wads of info on ADHD and its link with gluten tests. In the meantime we decided to go ahead anyway, particularly as there appeared to be suspect family background; (Lewie and Kate are from a long line of Berserks!), (in-house joke, both have the same birthday).
Within one week we couldn't believe the change coming over Lewen. He began to laugh a lot more, appetite improved, overt affection to all family members. Were we just imagining it? We decided to withhold medication to see what would happen. Nothing! No outrageous behaviour, just a really pleasant kid albeit still a live wire. Rather than let him feel different, it was one in all in; a gluten-free family.
Six weeks have passed with interesting results. Relenting after constant harassment from Nick we smuggle him in some bread buns and hide them in the freezer. Somewhere along the way, Lewie discovered them and we immediately noticed a change in his behaviour. Three-year-old Brent asked, "Is Lewie medicated, Mum?" Serves us right, but it did demonstrate to especially Nick, now fourteen, the importance of staying gluten-free and that in all probability, he was also affected.
We were lucky enough to see the dramatic results on a five year whose system is more sensitive to change. We know we are all going to benefit because we have witnessed it in Lewen. It is now six since we first went gluten-free and we have just got the first blood test result. Negative! Thank Christ we didn't wait to look for some reason to at least try it. It really does work. Shame about all those foods denied but a new adventure shopping and surprisingly better value for money and healthier. Kate considers herself a fantastic cook, but to be suddenly told that she couldn't use the BROW (barley, rye, oats, wheat) products to cook with, she was devastated! Six weeks later however, she can now make absolutely anything she made before - but now all gluten-free! She finds being gluten-free no problem at all!
Cheers, Ron - and thanks!
Kate and Frank
Sender: Celiac/Coeliac Wheat/Gluten-Free List
Poster: Carol Leather
Subject: Overweight and temper tantrums summary
Hi everyone,
Sorry I've taken a while to summarise all the replies to my last posting regarding my son's behaviour problems but I've been feeling pretty lousy this last week.
We have been having trouble with his volatile temper for a number of years but (how stupid can you get?) had never connected it with CD although I have it. Many of you wrote with similar experiences and advised me to get him checked out. I took him to the doctor's yesterday and she has agreed it may be a possibility (but coeliacs only get diarrhoea, was her first comment!) and will now organise blood tests.
Some stories sounded so familiar and everyone was so helpful. I was unsure wether to change his diet to see what happened but Chris wrote "DO NOT cut back on your son's gluten intake prior totesting .. as the antibody tests and intestinal biopsy can show very normal IF there's been substantial heling from lack of gluten intake." Thanks Chris for your reassurance that I was not the only overweight coeliac.
My thanks also to D Lynne your story sounded so much like ours. Ben has had similar violent outbursts at school and once picked up a chair and threatened the teacher with it!
jill mentioned that her child also seemed ever hungry but did not gain weight as did Kathy in her reply.
If I mention everyone who responded this post will be too long to read, so can I say thanks to you all.
I'll be away from the computer next week when i go in for my gallstone operation but will eagerly await the time when I can catch up on all your posts. Speak to you soon.
Carol Leather
An English Coeliac
Gluten is a Dubious Luxury of Non-Celiacs
by Ron Hoggan
(Note: In this paper I use the term "gluten" generically, as we celiacs use it, to refer to all toxic proteins in cereal grains.)
One must wonder why, in spite of increasing life-spans in the advanced industrialized nations, modern medicine has failed to clearly identify the cause of many neurological, autoimmune and malignant disease. The gluten-free diet is only recommended where there is a clear indication of advanced, gluten-induced disease, but is this the best advice?
We often feel disadvantaged by the strict gluten-free diet we have to follow. But perhaps it is those who continue to consume glutinous foods who should be feeling badly about their diets. Gluten, while dangerous to celiacs, has never been investigated for deleterious effects on the general population. Yet we have studies that show that hunter-gatherers following traditional life-ways do not develop the neurological, auto-immune and malignant diseases that people living in the industrialized world experience, and these people rarely eat gluten-rich foods (1,2). There is already compelling evidence connecting the advent of agriculture to bone and joint disease (3), and humankind has only been cultivating cereal grains for approximately 10,000 years (2,4), which is but a brief moment in evolutionary terms. Remember too, it is only a small population located in the Near East, that has had that length of exposure to cereal grains (4); most of the world has had agriculture for an even shorter period of time. Neurological and auto-immune diseases, as well as malignancies, are over-represented among celiacs (5), suggesting that glutens/gliadins may be a major environmental contributor to such diseases. Yet this area of investigation appears to have been avoided in research on these health problems. One must wonder at the cause of this neglect of such an important possibility.
We know, from the studies by palenotologists of human remains from the ancient past, that when a culture begins to cultivate cereal grains there is an overall reduction in height, which is variously reported as 5" and 6"(2,4). Clearly, the reduction is substantial and significant. We know, too, that these remains demonstrate weaker bone structure (through reductions in peak bone-mass) and evidence of articular damage(3). Additionally, ancient Egyptians, who consumed a diet that would be considered very "heart-healthy" in our culture, have left behind mummies which clearly demonstrate atherosclerosis (7). While the evidence from the ancients is compelling, there can always be counter-arguments and debates when we are reaching back as far as 10,000 years into the past. Yet a few marginal pockets of scientific enquiry have explored a few elements of modern implications of this issue.
W.J.Lutz (4) has offered an alternative perspective on the "French Paradox." (The "French Paradox" is the unusually low rate of death by myocardial infarction among the French despite quite high per-capita rates of fat consumption.) Dr. Lutz has studied the spread of agriculture through Europe. He presents a picture whereby the spread of agriculture, and thus the period of time a culture has been exposed to cereal grains, is inversely related to the incidence of cardiovascular disease. The underlying assumption, of course, is that the longer the exposure, the greater the likelihood that those who were intolerant to these grains were trimmed from the gene pool of such cultures; it seems that the less time a culture has been exposed to gluten, the greater the portion of the population that continues to develop cancers and cardiovascular disease. (Lutz also provides similarly compelling data on the rates of breast cancer mortality.)
A study done in China produced what the investigators found to be rather surprising results(8). In this investigation, the researchers plotted the diets of more than 3500 rural Chinese women, and measured their levels of SHBG (sex-hormone binding globulins) which are quite reliable predictors of cardiovascular disease. They were very surprised to find that wheat consumption, and perhaps, reduced fish consumption, were the strongest predictors of levels of SHBG which would indicate an increased risk of cardiovascular disease.
Another study has connected gluten with neurological illness (9). This group of researchers tested 53 patients with neurological illness of unknown origin for antibodies against gliadin. More than half of them (30 people) demonstrated these antibodies. Nine of those folks proved to have celiac disease, but the other 21 only demonstrated an immune response to gluten. This study has some far-reaching implications for neurological research.
Yet another indication that celiacs are not the only segment of the population to suffer from the adverse effects of gluten is a study that was carried out on a very small group of siblings of celiacs(10). When subjected to rectal gluten challenge, half of the siblings showed an immune response to gluten, but these results did not correlate with the hereditary predictors of celiac disease.
As for the connection between autoimmunity and cereal grains, it is clear and compelling. The theoretical perspective of molecular mimicry suggests that gliadin-derived peptides, due to their structural similarity to to the Epstein-Barr virus, may activate the immune system. Since the invading gliadin peptides lodge in collagenous tissues, and since only intestinal permeability (not celiac disease) is all that is requried to allow the passage of these peptides into the bloodstream, a significant number of many types of autoimmune diseases seem likely to benefit from a gluten-free diet(11).
In total, then, there are several studies which demonstrate (often coincidentally) that a much larger group than those with celiac disease are mounting an immune response against gluten, and that this response is causing or contributing to serious illness. Phytic acid in whole cereal grains binds to minerals, including calcium, and may be implicated in osteoporosis (12). Molecular mimicry may, as a result of gliadin peptides having similar molecular structures to the Epstein-Barr virus, provide a starting point for autimmunity, especially since gliadin peptides have demonstrated an affinity for collagenous tissue.
I would now like to draw your attention back to the issue of malignancy. _Medical Hypotheses_, a peer reviewed journal, has been kind enough to accept, for publication, a paper I have written which suggests (among other things) that gluten may be implicated in a great many cases of lymphoma(14). Gluten has been demonstrated to interfere with the celiac patient's ability to mount an immune response to malignancies(15,16,17). In my paper, I have postulated a dynamic whereby gluten may have a similar effect in others who are simply sensitive to gluten.
We hear all the time about pollution in the industrial world being the source for modern man's high incidence of cancer. It is the chemical additives, we are told, in the food we eat, that causes much of the problem. Dietary fats have also come under attack. I would like to suggest that the evidence from antiquity, the pattern of the spread of agriculture in Europe coinciding with the patterns of civilizatory illnesses, the levels of SBHG associated with wheat consumption, the high incidence of gliadin antibodies among those with neurological illnesses of unknown origin, the sensitivity to gluten among siblings of celiacs in spite of the absence of genetic indicators associated with celiac disease, and my own investigation of the literature regarding lymphoma, all point to the strong possibility that gluten is a dangerous substance to many more people than just celiacs.
Sources:
Dr. Kumar has been working on serological testing for celiac disease over the last 15 years, and was presenting after having been up all night trying to catch a flight from Buffalo after a severe snow storm. We were all pleased by his dedication, as his presentation was both informative and compelling. He began by asking some fundamental questions, which challenged several common beliefs about the diagnosis of celiac disease, beginning with: "Can we effectively diagnose celiac disease by its clinical presentations?" The answer came in the data he cited from Campbell & Davidson in their survey of 1300+ celiac patients. The first item indicated that celiac disease may present with a broad variety of symptoms, and are easy for clinicians to miss. The second item indicated that the majority had visited 5 or more doctors prior to diagnosis. The third item indicated that it had taken an average of 5 to 10 years, after initial presentation, for celiac disease to be diagnosed. Clearly, the answer to Dr. Kumar's question was that celiac disease can not be diagnosed by its clinical presentations. What would be the value of histological, or any other evidence, if it could be diagnosed on the basis of clinical presentation alone? He mentioned the considerable risk of misdiagnosis as well. While clinical presentation may help in identifying the possibility of celiac disease, it can not, reasonably, be the sole criteria for an accurate diagnosis. "Why do we need an early diagnosis of celiac disease?" was his next question. The answer was twofold. First, young children may not grow and develop properly if they have unidentified celiac disease. Normal development, for many of these children, requires that they be on a gluten-free diet, thus recieving adequate nutrition. Second, untreated celiac disease is associated with a very high risk of lymphoma, and the gluten free diet plays a protective role against lymphoma. It reduces the risk to almost the same as the general population, after 5 years on a strict diet He cautioned that less than 5 years may not yeild statistically significant reductions in risk. Similar risk factors for malignancy are at work in dermatitis herpetiformis. Histopathology gained acceptance in the mid-sixties, to aid in the diagnosis of celiac disease, because of the problems with diagnosis on the basis of clinical presentation. This is where a biopsy is taken from the small intestine, and the morphology is examined to determine the status of villi in the patient. Slides were shown, first demonstrating normal morphology of healthy villi, then demonstrating total villous atrophy, along with crypt hyperplasia, and increased density of intraepithelial lymphocytes. These were the criteria proposed in the mid-sixties, but such morphology alone is not diagnostic of celiac disease. Many other diseases like parasitic infections, immune deficiency disorders, and nutritional deficiency disorders, all look quite similar. At that time, ESPGAN (European Society of Gastroenterology and Nutrition) proposed a strict set of diagnostic criteria for celiac disease. First, characteristic flat or damaged villi were to be demonstrated. Second, after a gluten-free diet for an extended period of time, when the patient was feeling normal, a second biopsy should be taken, showing villi of normal appearance. Finally, a gluten-containing diet would be re-instituted, and if after a period of about 6 months, if villous atrophy was demonstrated at biopsy, then the diagnosis of celiac disease was confirmed. In many of the patients he has seen, there are poblems getting them to eat enough gluten to confirm the diagnosis for the third biopsy. Then there is the limitation that initially, patients need to be identified as needing the biopsy. Yet another limitation of this approach is that when a biopsy is taken, it is removed from a small, localized area. It may miss a region of typical celiac intestinal lesion and take the sample from a region showing very mild symptoms which are difficult to identify. These histological criteria are on a continuum, showing flat villi at one end, and normal villi at the other. Yet another limitation arises in the three recent reports which identify celiac disease in patients with normal histopathology. Pathologists apparently read them as normal biopsies. He cited papers from 1982, 1993 and 1996. Dr. Kumar used the iceburg metaphor to describe the current status of recognition of celiac disease, where the vast majority of celiac disease remains undiagnosed. We are seeing only typical celiac disease. This is where weight loss, diarrhea, short stature, very typical manifestations, lead to the biopsy, where the histology reveals characteristic damaged villi. What remains under the surface is two large groups: 1) silent celiac disease where the the patient presents with mild, atypical manifestations like low levels of iron and low haemoglobin levels. Some patients only present with aphthous ulcerations in their mouths but if they are tested, many of them demonstrate characteristic histopathology; 2) Then you have situations where patients who really have celiac disease, but if you test them, they show normal histopathology. What can be done, then? When it was first identified, in the 1960's that the gliadin proteins in wheat were the toxic entities in celiac disease, many investigators in Europe began looking for anti-gliadin antibodies. For serology to be effective, the techniques have to be very refined and well standardized. Otherwise, one lab reporting results may not be as good as another lab reporting results. Dr. Kumar reported on his own lab results in anti-gliadin antibody tests. He indicated that 5% to 10% of those demonstrating IgG anti-gliadin antibodies do not have celiac disease. Rarely, on the other hand, are IgA anti-gliadin antibodies demonstrated in non-celiacs. These antibodies are detected by very simple methods. The consensus in the field is that IgG antibodies are more sensitive, but not specific, and IgA antibodies are more specific but less sensitive. The next antibody identified in the literature was the antireticulin antibody. We don't really know what protein antigen this antibody is developed in response to. The name is a serological term, but it reacts to substances called reticulin which is in the tissues surrounding the tubules in the kidney. There are five types of reticulin antibodies. Only one of these is associated with celiac disease, and this is not a very sensitive marker, but it is very specific for celiac disease. When a patient goes on a g-f diet, their antibody levels will eventually disappear and become negative. The third type of antibody, reported in 1984, was the endomysial antibody. It is named in reference to the endomysium which is the lining of the muscle fibers. These, and the antireticulin antibodies are primarily of IgA class. In situations where patients are IgA deficient, they will make IgG antibodies. Patients with celiac disease demonstrate this antibody with virtually 100% frequency. On a gluten-free diet, these antibody levels become normal, or negative. They are a very sensitive, very specific marker of celiac disease. It takes varying periods for these levels to become normal. They reappear very quickly on a gluten challenge. He then reported on 133 celiac patients, 132 of whom showed IgA antiendomysium antibodies when eating gluten. The one who did not was IgA deficient, and was positive for IgG endomysial antibody. IgA is the more sensitive marker. All of the 133 patients eventually demonstrated negative levels of antiendomysial antibodies. When rechallenged with gluten 130 once again became positive for antiendomysial antibodies. Other studies indicate that if the other 3 were challenged with a high gluten-containing diet, they would have demonstrated antibodies too. Another group of 31 showed abnormal biopsies, but endomysial antibodies were not demonstrated. On a gluten-free diet, the the villous morphology returned to normal, but could not be induced again on gluten challenge. Neither were antiendomysial antibodies detected. It appears that these were not cases of celiac disease. A single biopsy can be misleading without additional evidence. Yet another group of patients in Italy, reported in 1996, demonstrated symptoms suggestive of celiac disease. They tested positive for antiendomysial antibodies, but did not display abnormalities in villous morphology. The question is, are these patients celiac or not? They demonstrated typical symptoms, which resolved on the gluten-free diet, and the endomysium antibodies also disappeared on the diet Upon gluten challenge, these symptoms returned, and the high antibody levels returned also. The clinical manifestations, including diarrhea, steathorrea, and abdominal cramping, are convincing evidence that these are cases of celiac disease in the early stages of immune response which, with time, will develop typical histology of celiac disease. Follow-up studies have demonstrated just this. There are certain HLA markers which are associated with celiac disease. Nine of ten celiac patients in another study did not have these markers. That means that the genetic markers we currently associate with celiac disease are also problematic. Lymphocyte density was also within the normal range. This indicates that these individuals are very early in their immune response. He used demonstrations of increased ICAM presentation in the same tissue, to indicate that an immune response was being mounted, but it was at a very early stage. If allowed to continue, Dr. Kumar was confident that the typical histopathology of celiac disease would eventually be demonstrated. He went on to show a study reported in _Acta Paediatrica_ where patients who demonstrated antiendomysial antibodies and normal mucosa, were re-biopsied three years later, and demonstrated villous atrophy. Quantity of gluten intake seems to be the primary variable, and where increased intake occurs villous atrophy follows. Examples reported as recently as 1994 indicate that diagnosis may still be slow among elderly patients, even where there is a threat to life. This demonstrates that diagnosis of celiac disease continues to be a very slow process in many cases. A simple serological test could help immensely. Among family members of those with celiac disease, symptomatic or asymptomatic celiac disease is present in 10% to 15% of first degree relatives. This is cd associated with short stature, autoimmune disorders and cardiac abnormalities. A simple serological test should be considered for family members. Dr. Kumar presented a compelling case for the value of serological screening for celiac disease. He indicated that the biopsy remains the gold standard for diagnosis, but I walked away from his presentation convinced that the serological testing offers earlier diagnosis, and thus improved health for celiac patients. We may be seeing the emergence of a new gold standard in the diagnosis of celiac disease; one which may reduce risk, be more reliable than the biopsy, and it is less invasive.
Ron,
You asked for it, so, as you have deadlines for your thesis, I'll take half an hour (How about an hour and a half!!!) and tell you a little bit about Clint, our older son, and the saga of his gluten sensitivity and the small part that ritalin plays in the story.
It all begins before he was born. As our first child, I didn't know what normal/abnormal in utero babies were like, so I assumed all the activity in my abdomen was normal. People thought I was exaggerating and making a fuss when I would jump and bend over backwards sometimes when he would kick and stretch before he was born. I had no choice - he needed more room and was hyperactive even then, and was very strong. With a second pregnancy, second son, I found how easy it is to carry a normal child. No extra bending backwards, no jumping around because I was so severely kicked.
After he was born, Clint was a difficult baby. At five days he came home from the hospital, fully able to support his own weight on his legs - to stand - as long as I kept him from falling over. Our best friend and neighbor was a doctor whose son was born three days later. He simply could not believe that Clint could stand at that age. But when the doctor held him, he found that it really was true.
He was always hungry, and never satisfied, and cried constantly. George and I walked the floor for hours, holding and patting and soothing and trying to be good parents. There were no pediatricians anywhere around, and as he appeared to be a 7 1/2 pound healthy baby, we thought WE must be doing something wrong. He was not nursed, and for years I felt guilty about that, but now that I know that he and I are both sensitive to gluten, I know that even if he had been nursed he would have been fussy. The OB had suggested putting him on food early, as he seemed fussy, so we started with rice cereal, then added probably oatmeal, (my memory is hazy on this sequence) and eventually pabulum, which, I believe, contains wheat. No particular additional problem with rice cereal, but no solution either. Some time after introducing pabulum he had a time with severe diarrhea. I think he had had that problem earlier, but I did not realize that it was abnormal. Then he developed thrush on his tongue and I got out Dr. Spock and a couple of other books. They both said to only feed rice cereal for a month or so - so I did just that, and the thrush went away. I believe we also eliminated formula (cow's milk based) for a few days. Then I put him back on regular baby pabulum, etc. The thrush did not return. I do not recall any virulent diarrhea from that time on, but it has been 44 years, and it's hard to reconstruct.
At three months he learned to suck his thumb - pacifiers did not work with him - and he finally was quiet George and I were so glad he wasn't crying we didn't care about the thumb. All along, he gained weight and looked healthy.
He never crawled, but slid around on his stomach like a salamander, and got where he wanted to go. He sat at the usual age. I know now that crawling is good for motor development, but I didn't know it then. At 14 months he walked, and started talking. By the age of 18 months he had an astonishingly large vocabulary - well over 250 words. I lost count after that, but he has always been eager to increase his vocabulary - even to this day.
At 14 months we moved, and sublet an apartment in Evanston, IL. Clint was so active we didn't dare spend much time in the apartment. He was so active NOTHING was safe - nor was he. He and I must have walked 10 miles a day - Clint being in and out of his stroller - just to keep him busy and out of harm's way.
Once he was walking I could not take him anywhere because he was so very active. Going to anyone else's home was a nightmare, I never could follow a conversation, nor would he play alone or with another child without grabbing, pushing, shoving, generally making everyone miserable. Yet he did not seem malicious - just seemed to have no control over what he did. As a result of this I had very few social contacts during his waking hours, and was too tired when he went to bed to have many friends or much social life.
When he entered kindergarten he was given an IQ test - I have only limited faith in those tests - and was found to be at the top end of the scale. Great - or at least encouraging. He did not, however, learn to read - in spite of having parents who read to him constantly. By the end of first grade we knew we were in trouble. His three 1/2 years younger brother was already reading more words than he could handle.
I have not talked about the nightmares. From probably age 2 on Clint had severe nightmares. He would awaken screaming and I'd go in to his room, pick him up, rock him and hold him until he would finally wake up, have a drink of water, slowly realize that he was safe and all was normal, then he would go back to sleep. That eventually became sleep walking and/or screaming nightmares. Those continued well into adulthood. In addition he ground his teeth at night and by the time he was 10 or so the dentist had put him in a plastic retainer type tooth guard, which he still wears. I honestly think he could throw the thing away, but he is so used to it he will not even try to sleep without it.
He did not learn to read in first, second, third, and fourth grades, altho he and I worked at home and he eventually had a basic reading vocabulary. It was agony for both of us, and sounding out a new word was painful and extremely frustrating for him. Fifth grade he was blessed with a newly graduated teacher who took a liking to him and tried to be of help. She would send home assignments for us to do together, and kept me informed about his work and what areas needed help. That began to build some badly needed self confidence. Recess and gym class were never comfortable, probably because he had never really learned how to play quietly with other boys without being too aggressive or too active.
A couple of things that have been left out. In first grade Clint became fascinated with math. He would put himself to sleep at night reciting addition tables, then subtraction, and still in first grade was teaching himself to multiply. By second grade he was dividing. [He's really good with computers!]
All this time we were moving from one town to another, one school system to another, one group of friends to another. Letting him go to preschool or early grade birthday parties was a nightmare, as he might accidentally break a birthday toy before the birthday child had a chance to play with it. Things were spilled, furniture tipped over. He just did not know how to play with other children.
I kept taking him to pediatricians and asking for help. "He would outgrow it." "He needed more sleep." " He needed more exercise." The crowning medical diagnosis was that "If his father is an engineer, that's probably the reason. They are much too aloof to be good parents." That was a corker! When you meet George you will meet a kind, gentle, and loving parent who spent as much time as he could, playing with his kids. He did not participate in the reading classes, but I can't fault him for that, as he had other things on his mind.
After first grade he was dropped into a slower class, and after second grade he was dropped into the slowest of the three third grade classes. This did not make a happy camper. Self-esteem plummeted.
I had read about dyslexia in an article in the Saturday Review of Literature, and decided that that was the problem. I also read about autism in Life Magazine and wondered if Clint was autistic, as he was so distant and difficult to reach at times. The dyslexia article gave suggestions about how to help those children learn, and I did everything they suggested, plus adding my own exercises and aids. The improvement was painfully slow.
Finally I read about ritalin and talked about that with the MD, who decided we could try it. That made a difference. I was, however, really very uncomfortable with using a strong drug that seemed to affect the brain, and in spite of a calming effect in the classroom, I decided not to continue with that. I don't know how I had the nerve to discontinue the medication, except that it seemed to turn him into a robot instead of my brilliant, if non-reading, son.
By seventh grade I finally had enough money to make an appointment at the University of Minnesota Child Development center. They spent a whole day giving Clint tests. He thought it was a ball, and at the end of the afternoon, when the professors were telling us what they had learned, he was busy showing me all the various block patterns he had put together for their tests, etc. The decision was that he was dyslexic and brilliant. [I could have told them that!] It was wonderful to have my positive feelings confirmed. They said that I should continue with what I had been doing, as it was obviously working, and that perhaps adolescence would make a change.
[It is interesting that young celiacs frequently have a remission during adolescence]
By the end of 7th grade he was reading a bit better. I would read mysteries to him and leave off the ending - some excuse about having to go iron or wash dishes. The book would stay next to the bed, and he would struggle thru the last two paragraphs. Then it was the last two pages, an eventually the last chapter. By the middle of 8th grade he was reading. By the beginning of 9th grade he was reading Shakespeare and loving it.
From then on he became a top student. One with absolutely awful hand writing, which persists to this day. And spelling is a mystery even now. I assume that visual memory and small muscle coordination are problem areas.
He was accepted by Cornell University and managed to graduate from the College of Liberal Arts in three years plus two summer sessions at the University of Minnesota. He knew we were really stretching to pay for Ivy League college education, and therefore took too many classes at once. But we promised the tuition money from the 4th undergraduate year for graduate school, so he then went to Northwestern University for and MBA.
As each college year began he would return to campus in good health, eating good meals with very little bread - we didn't go in for sandwiches, doughnuts, spaghetti, hamburgers, and pizza at my house. By the end of the school year he would return looking haggared and exhausted, a little slow of speech and definitely not relating well to others. In addition he had very little stamina for sports.
He is a handsome fellow. However, after graduating with his MBA, he could not get a job - did not interview well - much too intense and driven, I'm sure. He went into the Peace Corps, lived in hot climates, ate bread and strong tea with lots of sugar, and came home after 2 years looking like death warmed over. He got and lost two jobs.
By then I was becoming aware that my lifetime of feeling a little different from others had turned into steatorrhea and constant irrational anger - another of Clint's symptoms. Fortunately one of the many doctors that I saw over a ten year period finally said that maybe it wasn't in my mind. Maybe I had Whipple's disease. I went to the library. Ah, blessed library! There, after reading about Whipple's and thinking the profile didn't fit, I continued reading in the area of gastroerterological illnesses and came to celiac. The lights went on, the bells rang! I took myself off gluten and within three days I felt as though I had just been born. I had always managed to cope with people and jobs and school, so my problems had never been as severe as Clint's, but I was not an easy person to be around. [I'd like to think that I am a little bit like him in intelligence, but that's never been tested...]
So then I learned about a nutritionist in Washington, DC, where my mother was living, and made an appointment with her. She recommended the ELISA test, and Dr. Jaffe, who developed that test, actually administered the test himself. A charming man. With those test results I was told to remove milk protein and milk sugar [butter is ok] and remove a few other foods from my diet - many of which have now been added back. I was also given a large list of vitamin and mineral supplements to take to make up for a leaky gut.
Next step was to convince Clint to try my new found solution. After returning from South America, he had seen many doctors at the Peace Corps' expense, and then at our expense, and they all said he was healthy. He even passed a hypoglycemia test, when I knew that he was about to explode with anger at me, and the doctor and the nurse, and everyone else in the waiting room, and only years worth of extreme self control kept the professionals from seeing what was happening.
So then we drove across the USA together and as he drove I read the book Brain Allergies by Philpott, and another book about Psycho-Nutrition by Carlton Frederichs aloud to him. Each time we came across any symptom that seemed related to him, we wrote down the offending food or the helpful vitamin or mineral supplement. When we arrived home, I went to the drug store and bought the lot, and that day we took him off gluten and added all those things at once. The next morning, for the first time in my life, I woke up to the sound of Clint singing downstairs. I simply couldn't believe my eyes when I saw him. The almost gray pallor that had always been his coloring was gone and he was rosy cheeked and smiling. The transformation was nothing short of miraculous. Of course we continued the gluten-free, vitamin-heavy process for a second day.
The next day was Sunday, and I announced that I was going to attend church as a kind of public acknowledgement of my feelings - we were not a church going family. Clint said he would go with me. George said he'd come, too. After the service I went to talk with a friend, George went to talk with another friend, and Clint went to congratulate the soloist. He asked her to go the theatre the following weekend, but she said she was going home to the farm for the summer Corn and Clover Festival (Hinckley, MN - population about 1000, max.). Somehow Clint managed to be invited to go along for the weekend. A year later they were married and now I have two lovely grandsons. She cooks gluten-free most of the time for the whole family, tho she spoils herself and the boys once in a while.
After Clint's transformation, I realized that for years I had managed our whole family in a way that tried to keep him calm and non-belligerent. By the time he was himself, or cured, or whatever the term is that applies, our younger son had grown up and left home, and many problems that were caused in his life were out of our hands. There are many regrets, but we are all just glad that the disease had been cured and Clint had become the person that had been hiding inside the difficult shell all those years.
If you are interested in details, it is extremely important for Clint to avoid gluten and also to remember to take B-Complex and extra niacin in order to stay healthy.
There, that's the long story of Clint Kennedy. He's a delightful 44 year old man who runs the Boy Scouts and the Rotary Club and the Church and is a candidate for political office or manages campaigns for other candidates, and was elected to the school board, .....You would like him. He accepts that he is gluten-sensitive and is very careful about his diet, but he will not go to doctors, as he feels they missed his diagnosis for so many years they are not worth the effort. Eventually that will probably catch up with him, and it concerns me. He also will not get involved with this LIST, but now does keep a file of information that I forward to him from the LIST. And I send recipes to his wife, Karen.
Anything else you need to know? I hope this has been helpful.
I'll be home until tomorrow around noon (I suppose that's 8 AM your time) and would be interested in your response. Think I'll send a copy of this to Clint.
Best of luck with the thesis. I think it would be a lot shorter with footnotes!!!
Gayle